Medical Policy: 02.04.56 

Original Effective Date: October 2009 

Reviewed: June 2020 

Revised: December 2019 

 

Notice:

This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.

 

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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.

 

Description:

Various genetic and protein biomarkers associated with prostate cancer may potentially improve the specificity of testing and diminish the probability of unnecessary biopsies. This evidence review addresses these types of tests for prostate cancer risk assessment and diagnosis.

 

In 2019, it is estimated that 174,650 men will be diagnosed with prostate cancer. The age adjusted death rates from prostate cancer have declined 51% from 1993 to 2016. Researchers have estimated that prostate cancer will account for 9.8% of male cancer deaths in 2018. (NCCN 2.2019). Prostate cancer is a complex, heterogeneous disease, ranging from microscopic tumors unlikely to be life-threatening to aggressive tumors that can metastasize, leading to morbidity or death. Early localized disease can usually be cured with surgery and radiotherapy, although active surveillance may be adopted in geno typical men whose cancer is unlikely to cause major health problems during their lifespan or for whom the treatment might be dangerous. In patients with inoperable or metastatic disease, treatment consists of hormonal therapy and possibly chemotherapy. The lifetime risk of being diagnosed with prostate cancer for geno typical men in the United States is approximately 16%, while the risk of dying of prostate cancer is 3%. African-American geno typical men have the highest prostate cancer risk in the United States; the incidence of prostate cancer is about 60% higher and the mortality rate is more than 2 to 3 times greater than that of geno typical white men. Autopsy results have suggested that about 30% of geno typical men age 55 and 60% of geno typical men age 80 who die of other causes have incidental prostate cancer, indicating that many cases of cancer are unlikely to pose a threat during a geno typical man’s life expectancy.

 

The most widely used grading scheme for prostate cancer is the Gleason system. It is an architectural grading system ranging from 1 (well differentiated) to 5 (poorly differentiated); the score is the sum of the primary and secondary patterns. A Gleason score of 6 is low grade prostate cancer that usually grows slowly; 7 is an intermediate grade; 8 to 10 is high grade cancer that grows more quickly.  Gleason scores are often grouped into simplified Grade Groups: Grade Group 1 = Gleason 6; Grade Group 2 = Gleason 3 + 4=7; Grade Group 3 = Gleason 4 + 3 = 7; Gleason Group 4 = Gleason 8; Gleason Group 5 = Gleason 9 or 10. Physicians look at the Gleason score/Grade Group in addition to stage to help plan treatment.

 

Numerous genetic alterations associated with development or progression of prostate cancer have been described, with the potential for the use of these molecular markers to improve the selection process of men who should undergo biopsy or rebiopsy after an initial negative biopsy.

 

For assessing future prostate cancer risk, numerous studies have demonstrated the association of many genetic and protein biomarker tests and prostate cancer. Commercially available tests include but are not limited to:

  • 4Kscore Test (kallikrein markers) (OPKO Lab): a blood test that measures 4 biomarkers (PSA, free PSA, intact PSA and hK2 [human Kallikrein-2]), which are combined into an algorithm with a patient’s age, optional digital rectal exam, and any prior biopsy history to give the physician a personal risk of aggressive prostate cancer to decide whether a patient should proceed to prostate biopsy or repeat prostate biopsy.
  • APIFINY (Armune BioScience): measures eight prostate cancer specific biomarkers (autoantibodies) ARF 6, NKX3-1, 5-UTR-BMI1, CEP 164, 3-UTR-Ropporin, Desmocollin, AURKAIP-1, CSNK2A2. These biomarkers (autoantibodies) are produced and replicated (amplified) by the immune system in response to the presence of prostate cancer cells. The autoantibodies are stable and, because of their amplifications, are likely to be abundant and easy to detect, especially with small tumors characteristics of early stage cancers. APIFINY should be used in combination with other accepted methods of patient management. In men with elevated PSA, APIFINY is designed to aid in the assessment of risk for prostate cancer and in the selection of patients for biopsy. APIFINY test process is performed in part using a qualitative immunoassay technique and in part using flow cytometry. The laboratory data generated by these methodologies are then subjected to a proprietary algorithmic analysis that generates a cancer risk score. APIFINY does not rely on PSA values.
  • ConfirmMDx (MDxHealth): measures hypermethylation of 3 genes (GSTP1, APC, RASSF1) in a negative prostate biopsy to determine whether a patient should undergo repeat biopsy.
  • ExoDx Prostate (IntelliScore)/ExosomeDx Prostate (IntelliScore) (Exosome Diagnostics, Inc): non-digital rectal exam (DRE) urine based liquid biopsy test that predicts the presence of high grade (Gleason score ≥ 7) prostate cancer for men 50 years of age and older with a PSA 2-10 ng/mL presenting for an initial biopsy. A “rule out” test ExoDx Prostate (IntelliScore) is designed to more accurately predict whether a patient presenting for an initial biopsy does not have a high grade prostate cancer and, thus could potentially avoid an initial biopsy and instead continue to be monitored. Using a proprietary algorithm that combines the relative weighted expression of the three gene signature, the test assigns an individual risk score for patients ranging from 0 to 100. A score > 15.6 is associated with an increased likelihood of high grade prostate cancer on a subsequent biopsy. Physicians can utilize the score in conjunction with the other standard of care prognostic information to determine whether to proceed with a tissue biopsy.
  • MI-Prostate Score (University of Michigan MLabs): urine test looks for the T2-ERG fusion (TMPRSS2: ERG) as well as another marker, PCA3. This is combined with the PSA measure to produce a risk assessment for prostate cancer. The test also predicts risk for having an aggressive tumor, helping doctors and patients make decisions about whether to wait and monitor test levels or pursue immediate biopsy. This can also be utilized in individuals who had a prior negative biopsy to determine if repeat biopsy should be performed.
  • Progensa PCA3 Assay (Gen-Probe now Hologic)/PCA3 tests (ARUP Laboratories: Mayo Medical Laboratories; LabCorp): urine test that measures the concentration of PCA3 mRNA and prostate-specific antigen (PSA) and calculates a ratio of PCA3 molecules to PSA molecules (PCA3 Score) in post-digital rectal exam (DRE) first catch male urine specimen. Progensa PCA3 Assay is indicated for use in conjunction with other risk indicators to aid in patient management in the "at risk" population of men 50 years of age or older who have had 1 or more previous negative prostate biopsies and for whom a repeat biopsy would be recommended by a urologist based on the current standard of care.
  • Prostate Core Mitomics Test (Mitomics (formerly Genesis Genomics): measures mitochondrial DNA mutations in a negative prostate biopsy to determine whether a patient should undergo repeat biopsy.
  • Prostate Health Index (PHI) (Beckman Coulter): is considered a PSA derivative or isoform and is used to evaluate the probability of prostate cancer diagnosis, it combines measurements of % free PSA, tPSA (total PSA) and pro2PSA into a single numerical score (phi score). This score gives more accurate information about what an elevated PSA level might mean and the probability of finding prostate cancer with a biopsy.
  • SelectMDx for Prostate Cancer (MDxHealth): helps identify patients at increased risk for aggressive disease, thereby aiding in the selection of men for prostate biopsy. SelectMDx for Prostate Cancer is a reverse transcription PCR (RT-PCR) assay performed on post-DRE (digital rectal examination), first void urine specimen from patients with clinical risk factors for prostate cancer, who are being considered for biopsy. The test measures the mRNA levels of the DLX1 and HOXC6 biomarkers, using KLK3 expression as internal reference, to aid in patient selection for prostate biopsy. Higher expression levels of DLX1 and HOXC6 mRNA are associated with an increased probability for high grade (Gleason Score (GS) ≥ 7) prostate cancer.
  • SNVs (Single Nucleotide Variant) testing: as part of genome-scanning tests for prostate cancer risk assessment are offered by a variety of laboratories, such as Navigenics (now Life Technologies) and ARUP (deCode), as laboratory developed tests.

 

Genetic and Protein Biomarker Testing for Selection of Men for Initial Prostate Biopsy

Clinical Context and Test Purpose

The purpose of genetic and protein biomarker testing for prostate cancer is to inform the selection of men who should undergo initial biopsy. Conventional decision making tools for identifying men for prostate biopsy include digital rectal exam (DRE), serum prostate specific antigen (PSA), and patient risk factors such as age, race, and family history of prostate cancer.

 

DRE has relatively low interrater agreement among urologists, with estimated sensitivity, specificity, and positive predictive value (PPV) for diagnosis of prostate cancer of 59%, 94% and 28%, respectively. DRE might have a higher PPV in the setting of elevated PSA.

 

The risk of prostate cancer increases with increasing PSA; an estimated 15% of geno typical men with a PSA level of 4 ng/mL or less and normal DRE, 30% to 35% of geno typical men with PSA level between 4 and 10 ng/mL, and more than 67% of geno typical men with PSA level greater than 10 ng/mL will have biopsy detectable prostate cancer. Use of PSA levels in screening has improved detection of prostate cancer. The European Randomized Study of Screening for Prostate Cancer (ERSPC) and Goteborg prostate screening trials demonstrated that biennial PSA screening reduces the risk of being diagnosed with metastatic prostate cancer.

 

However, elevated PSA levels are not specific to prostate cancer; levels can be elevated due to infection, inflammation, trauma, or ejaculation. In addition, there are no clear cutoffs for cancer positivity with PSA. Using a common PSA level cutoff of 4.0 ng/mL, the American Cancer Society (ACS) systematically reviewed the literature and calculated pooled estimates of elevated PSA sensitivity of 21% for detecting any prostate cancer and 5% for detecting high-grade cancers with estimated specificity of 91%.

 

PSA screening in the general population is controversial. In 2018, the U.S. Preventive Services Task Force updated their recommendation against PSA-based screening for men ages 55-69 and men age 70 and older (C recommendation/D recommendation), while guidelines published by American Cancer Society (ACS) and the American Urological Association (AUA) endorsed consideration of PSA screening based on age, other risk factors, estimated life expectancy and shared decision making.

 

The utility of PSA screening depends on whether screening can lead to management changes that improve net health outcome. Results from the National Health Services supported Prostate Testing for Cancer and Treatment Trial (2016) demonstrated no difference in 10 year prostate cancer mortality rates between the treatment strategies of active monitoring, radical prostatectomy, and external beam radiotherapy in clinically localized prostate cancer detected by PSA testing.

 

Existing screening tools have led to unnecessary prostate biopsies. More than 1 million prostate biopsies are performed each year in the United States with a resulting cancer diagnosis in 20% to 30% of geno typical men. About one-third of geno typical men who undergo prostate biopsy experience transient pain, fever, bleeding, and urinary difficulties. Serious biopsy risks, such as bleeding or infection requiring hospitalization, are rare with estimates of rates ranging from less than 1% to 3%.

 

Given the risk, discomfort, and burden of biopsy and low diagnostic yield, there is a need for noninvasive tests that distinguish potentially aggressive tumors that should be referred for biopsy from clinically insignificant localized tumors or other prostatic conditions that do not need biopsy with the goal of avoiding low yield biopsy.

 

Patients

The relevant populations of interest are geno typical men for whom an initial prostate biopsy is being considered because of clinical symptoms such as difficulty with urination or elevated PSA.

 

The population for which these tests could be most informative is geno typical men in the indeterminate or “gray zone” range of PSA on repeat testing with unsuspicious DRE findings. Repeat testing of PSA is important because results of repeat testing of PSA levels initially reported to be between 4 and 10 ng/mL are frequently normal. The gray zone for PSA levels is usually between 3 or 4 and 10 ng/mL, but PSA levels varies with age. Age-adjusted normal PSA ranges have been proposed but are not standardized or validated.

 

Screening of geno typical men with a life expectancy of less than 10 years is unlikely to be useful because most prostate cancer progresses slowly. However, the age range for which screening is most useful is controversial.

 

Comparators

Standard clinical examination for determining who goes to biopsy might include DRE, review of history of PSA values, along with consideration of risk factors such as age, race, and family history. The ratio of free or unbound PSA to total PSA is lower in geno typical men who have prostate cancer than in those who do not. A percent free PSA (%fPSA) cutoff of 25% has been shown to have sensitivity and specificity of 95% and 20% respectively for geno typical men with total PSA values between 4.0 ng/mL and 10.0 ng/mL.

 

The best way to combine all of the risk information to determine who should go to biopsy is not standardized. Risk algorithms have been developed that incorporate clinical risk factors into a risk score or probability. Two examples are the Prostate Cancer Prevention Trial (PCPT) predictive model and the Rotterdam Prostate Cancer risk calculator (also known as the European Research Screening Prostate Cancer Risk Calculator 4 (ERSPC-RC). The American Urological Association (AUA) and the Society of Abdominal Radiology's prostate cancer disease-focused panel recently recommended that high quality prostate MRI, if available, should be strongly considered in any patient with a prior negative biopsy who has persistent clinical suspicion for prostate cancer and who is under evaluation for a possible repeat biopsy.

 

Outcomes

The beneficial outcome of the test is to avoid a negative biopsy for prostate cancer. A harmful outcome is failure to undergo a biopsy that would be positive for prostate cancer, especially when disease is advanced or aggressive. Therefore, the relevant measures of clinical validity are sensitivity and negative predictive value (NPV). The appropriate reference standard is biopsy, though prostate biopsy is an imperfect diagnostic tool. Biopsies can miss cancers and repeat biopsies are sometimes needed to confirm the diagnosis. Detection rates vary by method used for biopsy and patient characteristics.

 

Timing

The timeframe of interest for calculating performance characteristics is time to biopsy result. Geno typical men who forgo biopsy based on test results could miss or delay diagnosis of cancer. Longer follow-up would be necessary to determine effects on overall survival.

 

Setting

Initial screening using PSA levels and DRE may be performed in the primary care setting with referral to specialty (urologist) care for suspicious findings and biopsy. Clinical practice on screening methods and frequency vary widely.

 

4Kscore Test

The 4Kscore test (OPKO Lab) is a blood test that generates a risk score estimating the probability of finding high-grade prostate cancer (defined as a Gleason Score ≥ 7) if a prostate biopsy were performed. The intended use of the test is to aid in the decision of whether or not to proceed with a prostate biopsy or repeat prostate biopsy. A kallikrein is a subgroup of enzymes that cleaves peptide bonds in proteins. The intact prostate-specific antigen (iPSA) and human kallikrein 2 (hK2) tests are immunoassays that employ distinct mouse monoclonal antibodies. The score combines the measurement of 4 prostate-specific kallikreins (total prostate specific antigen (tPSA), free PSA (fPSA), intact PSA (iPSA), and human kallikrein 2 (hK2), with an algorithm including patient age, digital rectal exam (DRE), and prior prostate biopsy history.

 

The manufacturer’s website states that the ideal patient for the 4Kscrore is one whose other test results are equivocal. The test is not intended for patients with a previous diagnosis of prostate cancer, who have had a digital rectal exam (DRE) in the previous 4 days of this test, who have received 5-alpha reductase inhibitor therapy in the previous 6 months (such as Avodart [dutasteride] or Proscar [finasteride], or has undergone within the previous 6 months any procedure or therapy to treat symptomatic benign prostatic hypertrophy (BPH) or any invasive urologic procedure that may be associated with a secondary PSA elevation.

 

Based on the 4Kscore Test U.S. validation study, prostate biopsy should be considered in most men with a 4kscore result of 7.5% or higher. Reference ranges are as follows:

  • Low risk: 4Kscore result < 7.5%
  • Intermediate Risk: 4Kscore result 7.5%-19%
  • High Risk: 4Kscore result ≥ 20%

 

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

 

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome of care can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary testing.

 

Based on National Comprehensive Cancer Network (NCCN) guideline Prostate Early Detection Version 2.2019, when a patient meets the standards for biopsy, sometimes the patients and physicians wish to further define the probability of cancer before proceeding to biopsy with its associated risks. Several biomarker tests have been developed with the goals of refining patient selection for biopsies, decreasing unnecessary biopsies, and increasing the specificity of cancer detection, without missing a substantial number of higher grade (Grade Group ≥ 2) cancers. These tests may be especially useful in men with PSA levels between 3 and 10 ng/mL. NCCN also notes that biomarkers that improve the specificity of detection are not recommended as first-line screening tests, rather for use in those individuals who wish to further define the probability of high-grade cancer.

 

Based on the NCCN 2A recommendation, the NCCN panel consensus is that the 4Kscore test can be considered for patients prior to biopsy who are thought to be at higher risk for clinically significant prostate cancer.

 

A prospective multi-institutional U.S. trial of 1012 patients showed that 4Kscore results have a high discrimination value (area under the curve (AUC), 0.82). In this study, using a threshold biopsy of ≥ 15% risk allowed for 591 biopsies to be avoided (58%), while 183 high-grade tumors were detected and 48 high grade tumors (4.7% of the 1012 participants) were missed. When 4Kscore was examined in 6129 men in another prospective study, the AUC was also 0.82 (95% CI, 0.80-0.84). Using a 6% risk of high-grade cancer cutoff, 428 of 1000 men could avoid biopsy, with 119 of 133 high grade cancers detected and 14 of 133 missed. A multi-center clinical utility study found a 65% reduction in prostate biopsies with use of 4Kscore test. In addition, a correlation between 4Kscore risk category and Gleason score was seen (P < .01). A meta-analysis that included 12 clinical validation studies (11,134 patients) led to a calculated pooled AUC for discrimination of prostate cancer with Gleason score of ≥ 7 of 0.81 (fixed effects 95% CI, 0.80-0.83).

 

Summary

The use of 4Kscore biomarker test is supported by published professional society guideline – National Comprehensive Cancer Network (NCCN) Prostate Cancer Early Detection 2.2019 as a 2A recommendation. When a patient meets the standards for biopsy, sometimes the patient and physicians wish to further define the probability of cancer before proceeding to biopsy with its associated risks. Several biomarker tests have been developed with the goals of refining patient selection for biopsies, decreasing unnecessary biopsies, and increasing the specificity of cancer detection, without missing a substantial number of higher grade (Grade Group ≥ 2) cancers. These tests may be especially useful in men with PSA levels between 3 and 10 ng/mL. NCCN also notes that biomarkers that improve the specificity of detection are not recommended as first-line screening tests, rather for use in those individuals who wish to further define the probability of high-grade cancer. The NCCN panel consensus is that the 4Kscore test can be considered for patients prior to biopsy who are thought to be at higher risk for clinically significant prostate cancer. The evidence is sufficient to determine the technology results in a meaningful improvement in net health outcome as indicated by the NCCN panel consensus.

 

Prostate Health Index (PHI) (proPSA)

The Prostate Health Index (phi) test (Beckman Coulter) utilizes a calculation that combines the results of 3 blood serum immunoassays (tPSA [total PSA], %fPSA [%free PSA] and proPSA [p2PSA]) into a single numerical result, the “phi score.” This score is calculated in a routine laboratory using Beckman Coulter equipment and software with phi algorithm incorporated in the software. This score gives more accurate information about what an elevated PSA level might mean and the probability of finding prostate cancer with a biopsy.

 

The phi score has been approved by FDA for distinguishing prostate cancer from benign prostatic conditions in men 50 years and older with total PSA (tPSA) readings ≥ 4.0 and ≤10.0 ng/mL, and with a digital rectal examination (DRE) findings that are not suspicious for cancer.

 

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

 

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome of care can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary testing.

 

Based on National Comprehensive Cancer Network (NCCN) guideline Prostate Early Detection Version 2.2019, when a patient meets the standards for biopsy, sometimes the patient and physicians wish to further define the probability of cancer before proceeding to biopsy with its associated risks. Several biomarker tests have been developed with the goals of refining patient selection for biopsies, decreasing unnecessary biopsies, and increasing the specificity of cancer detection, without missing a substantial number of higher grade (Gleason ≥ 7) cancers. These tests may be especially useful in men with PSA levels between 3 and 10 ng/mL. NCCN also notes that biomarkers that improve the specificity of detection are not recommended as first-line screening tests, rather for use in those individuals who wish to further define the probability of high-grade cancer.

 

Based on the NCCN 2A recommendation, the NCCN panel recommends the Prostate Health Index (PHI) test can be considered before initial biopsy in men with serum PSA levels of > 3 ng/mL who desire more specificity.

 

In a multicenter study, Prostate Health Index (PHI) was noted to have approximately double the sensitivity of fPSA/tPSA for cancer detection in those with serum PSA concentrations between 2 and 10 ng/mL. In addition, the PHI correlated with cancer grade and had an area under the curve (AUC) of 0.72 for discrimination of high grade (Gleason ≥ 7) cancer from low grade cancer or negative biopsy. Another prospective cohort study calculated an AUC of 0.815 for the detection of high-grade (Gleason Score ≥ 7) prostate cancer. This study determined the optimal cutoff of PHI to be a score of 24, which should lead to 36% of biopsies avoided with approximately 2.5% of high grade cancers missed. Other studies have also shown that PHI can predict aggressive prostate cancer and has potential clinical utility.

 

A clinical utility study conducted at 4 large urology group practices showed that use of PHI was in fact associated with a decrease in biopsy procedures performed when compared to historical controls from the same physicians (36.4% vs 60.3%; P < 0.0001). Patients in the study had a normal DRE and PSA values ranging from 4 to 10 ng/mL. Physician survey results showed that PHI results impacted biopsy decisions in 73% of cases.

 

Summary

The use of Prostate Health Index (PHI) (proPSA) biomarker test is supported by published professional society guideline – National Comprehensive Cancer Network (NCCN) Prostate Cancer Early Detection 2.2019 as a 2A recommendation. When a patient meets the standards for biopsy, sometimes the patient and physicians wish to further define the probability of cancer before proceeding to biopsy with its associated risks. Several biomarker tests have been developed with the goals of refining patient selection for biopsies, decreasing unnecessary biopsies, and increasing the specificity of cancer detection, without missing a substantial number of higher grade (Grade Group ≥ 2) cancers. These tests may be especially useful in men with PSA levels between 3 and 10 ng/mL. NCCN also notes that biomarkers that improve the specificity of detection are not recommended as first-line screening tests, rather for use in those individuals who wish to further define the probability of high-grade cancer. The NCCN panel recommends the Prostate Health Index (PHI) test can be considered before initial biopsy in men with serum PSA levels of > 3 ng/mL who desire more specificity. The evidence is sufficient to determine the technology results in a meaningful improvement in net health outcome as indicated by the NCCN panel recommendation.

 

APIFINY

APIFINY technology is based on the measurement of eight prostate cancer specific biomarkers (autoantibodies) ARF 6, NKX3-1, 5-UTR-BMI1, CEP 164, 3-UTR-Ropporin, Desmocollin, AURKAIP-1, CSNK2A2. These biomarkers (autoantibodies) are produced and replicated (amplified) by the immune system in response to the presence of prostate cancer cells. The biomarkers (autoantibodies) are stable and, because of their amplifications are likely to be abundant and easy to detect, especially during the early stages of cancer.

 

Given the complexity of cancer risk assessment, obtaining additional information may provide insight to better inform an important clinical decisions such as an initial or repeat biopsy:

  • APIFINY may be used in men who have an elevated PSA (> 2.5 ng/ml) and are considering a prostate biopsy.
  • APIFINY may aid in the assessment of prostate cancer risk.
  • APIFNY test results aid in making decisions regarding the right monitoring or cancer detection program.

 

Statistical analysis shows there is an interdependence among the biomarkers (autoantibodies). Three of the biomarkers are associated with androgen-response regulation, and four are related to cellular structural integrity. The eighth biomarker has been implicated in prostate cancer progression and a variety of cellular functions ranging from cellular signaling for numerous protein kinases to regulating cell cycle and cell division. The APIFINY test process is performed in part using a qualitative immunoassay technique and in part using flow cytometry. The laboratory data generated by these methodologies are then subjected to a proprietary algorithmic analysis that generates a cancer risk score. APIFINY score reporting was designed to optimize the identification of patients at lower risk. Patients with a lower risk APIFINY score may be placed on a routine clinical monitoring program (i.e. semi-annual or annual check-up) with other accepted methods to assess the ongoing risk of prostate cancer. Geno typical men with higher APIFINY scores may require a more specific risk-assessment plan, which may include biopsy. Scores below 59 are considered lower relative risk, scores at or above 59 have a higher relative risk of prostate cancer.

 

Summary

Two studies have been done, a biomarker selection/algorithm development study and a clinical validation study. 519 samples were used in the biomarker selection/algorithm development study and 259 different samples were used in the clinical validation study. Although the studies are promising research has not yet been completed in determining the effects of age, race or other factors on the APIFINY score. Further studies are needed to determine the effects of demographics such as age, race or other factors on the APIFINY score and for clinical utility. Clinical utility of APIFINY test is uncertain, currently there is no evidence that the use of APIFINY tests can change management in ways that improve outcomes. NCCN guideline 2.2019 Prostate Cancer Early Detection, does not discuss or indicate the use of the APIFINY test within this guideline. The evidence is insufficient to determine the effects of this technology on net health outcomes.

 

ExoDx Prostate (IntelliScore)

ExoDx Prostate (IntelliScore), also called EPI, is a non-digital rectal exam (DRE) urine based liquid biopsy test that predicts the presence of high grade (Gleason score ≥ 7) prostate cancer for men 50 years of age and older with a PSA 2-10 ng/mL presenting for an initial biopsy. A “rule out” test ExoDx Prostate (IntelliScore) is designed to more accurately predict whether a patient presenting for an initial biopsy does not have a high grade prostate cancer and, thus could potentially avoid an initial biopsy and instead continue to be monitored. Using a proprietary algorithm that combines the relative weighted expression of the three gene signature, the test assigns an individual risk score for patients ranging from 0 to 100. A score > 15.6 is associated with an increased likelihood of high grade prostate cancer on biopsy. Physicians can utilize the score in conjunction with the other standard of care prognostic information to determine whether to proceed with a tissue biopsy.

 

McKiernan et. al. (2016) studied the performance of novel urine exosome gene expression assay (the ExoDx Prostate IntelliScore urine exosome assay) plus standard of care (SOC) (i.e. prostate specific antigen (PSA) level, age, race and family history) versus SOC alone for discriminating between Gleason score 7 and 6 and benign disease on initial biopsy. In training, using reverse transcriptase polymerase chain reaction (PCR), they compared the urine exosome gene expression assay with biopsy outcomes in 499 patients with prostate-specific antigen (PSA) level of 2 to 20 ng/mL. The main outcomes and measures was evaluating the assay using the area under receiver operating characteristic curve (AUC) in discrimation of GS7 or greater from GS6 and benign disease on initial biopsy. In 255 men in the training target population (median age 62 years and median PSA level 5.0 ng/mL, and initial biopsy), the urine exosome gene expression assay plus SOC was associated with improved discrimination between Gleason score 7 or greater and Gleason score 6 and benign disease. Area under the curve (AUC) 0.77 (95% CI, 0.71-0.83) versus SOC ACU 0.66 (95% CI, 0.58-0.72) (P<.001) Independent validation in 519 patients urine exosome gene expression assay plus SOC AUC 0.73 (95% CI, 0.68-0.77) compared to SOC AUC 0.63 (95% CI, 0.58-0.68) (P<.001). Using a predefined cut point, 138 of 519 (27%) biopsies would have been avoided, missing only 5% of patients with dominant pattern for high risk Gleason score 7 disease. The authors concluded this urine exosome gene expression assay is a noninvasive, urinary 3-gene expression assay that discriminates high grade (>GS7) from low-grade (GS6) cancer and benign disease. In this study, the urine exosome gene expression assay was associated with improved identification of patients with higher grade prostate cancer among men with elevated PSA levels and could reduce the total number of unnecessary biopsies.

 

In 2018, McKiernan et. al. report on the second validation of a prospective, two-cohort, adaptive clinical implementation and utility study of the ExoDx Prostate (IntelliScore) (EPI) urine exosome gene expression assay comparing EPI results with biopsy outcomes. Eligible participants had not been diagnosed with prostate cancer (PCa), were aged ≥ 50 years with a PSA 2-10 ng/mL, and scheduled for their initial prostate needle biopsy. After completion of cohort 1, a clinical implementation document (i.e. CarePath) was developed for utilizing the EPI score in a second phase patient cohort, where the biopsy decision is uncertain. In a total of 503 patients, with median age of 64 yr, median PSA 5.4ng/ml, 14% African American, 70% Caucasian, 53% positive biopsy rate (22% GG1, 17% GG2, and 15% ≥ GG3), EPI was superior to an optimized model of standard clinical parameters with an area under the curve (AUC) 0.70 versus 0.62, respectively, comparable with previously published results (n=519 patients, EPI AUC 0.71). Validated cut-point 15.6 would avoid 26% of unnecessary prostate biopsies and 20% of total biopsies, with negative predictive value (NPV) 89% and missing 7% of ≥GG2 PCa. Alternative cut-point 20 would avoid 40% of unnecessary biopsies and 31% of total biopsies, with NPV 89% and missing 11% of ≥GG2 PCa. The clinical investigators reached consensus recommending use of the 15.6 cut-point for phase II. Outcome of the decision impact cohort in phase II will be reported separately. The authors concluded, EPI is a noninvasive, easy-to-use, gene expression urine assay, which has now been successfully validated in over 1000 patients across two prospective validation trials to stratify risk of ≥GG2 from GG1 cancer and benign disease. The test improves identification of patients with higher grade disease and would reduce the total number of unnecessary biopsies.

 

The authors of the above study also included the following patient summary: It is challenging to predict which men are likely to have high-grade prostate cancer (PCa) at initial biopsy with prostate-specific antigen 2-10ng/ml. This study further demonstrates that the ExoDx Prostate (IntelliScore) test can predict ≥GG2 PCa at initial biopsy and defer unnecessary biopsies better than existing risk calculator's and standard clinical data.

 

NCCN Guideline Version 2.2019 Prostate Cancer Early Detection, includes the following regarding this test: ExoDx Prostate (IntelliScore), also called EPI, evaluates a urine-based 3 gene exosome expression assay utilizing PCA3 and ERG (V-ets erythroblastosis virus E26 oncogene homologs) RNA from urine, normalized to SPDEF (SAM pointed domain-containing ETS transcription factor). The background for these markers is supported by a number of studies, but the application to exosome detection is unique. This gene panel proposes to discriminate Grade Group ≥ 2 prostate cancer from Grade Group 1 and benign disease at initial biopsy. The population for which use of the assay was intended includes patients older than 50 years with no prior biopsy and a PSA value between 2 and 10 ng/mL. In a recent study by McKiernan et. al., estimates of the AUC were similar in the training (0.74) and validation (0.71) cohorts for the assay, with significant improvements when the test was added to standard of care variables alone. Applying a cutoff value from the training cohort to serve as a threshold for biopsy in the validation cohort decreased the need for biopsy by 27% (138 of 519) while missing 8% (12 of 148) of Grade Group ≥ 2 cancers. The investigators propose the assay as a secondary or reflex test for risk stratification in conjunction with PSA screening. In the McKiernan study, the algorithm was validated in a test set of 255 patients and then validated in the extended screening validation cohort of 519 patients. The majority of exclusions were for urine volume > 49 mL, assay failure, and application outside the intended use population. A second independent validation study was a 2 phase adaptive clinical utility study that included 503 biopsy-naive patients with PSA levels between 2 and 10 ng/mL and compared EPI and biopsy results. In the first phase of this study, the AUC was 0.70 for predicting Grade Group ≥ 2 cancer by EPI. Using the validated cut-point 15.6, the test has an NPV of 89%, reducing total biopsies by 20% and missing 7% of Grade Group > 2 cancer. The second phase of this trial will be reported in the future. The panel believes that EPI can be considered as an option for men contemplating initial or repeat biopsy.

 

Summary

It is challenging to predict which men are likely to have high-grade prostate cancer (PCa) at initial biopsy with prostate-specific antigen 2-10ng/ml. Based on review of the peer reviewed medical literature, the limited evidence demonstrates that the ExoDx Prostate (IntelliScore) test can predict ≥ Grade Group 2 Pca (prostate cancer) at initial biopsy and defer unnecessary biopsies better than existing risk calculator's and standard clinical data. NCCN guideline Prostate Cancer Early Detection Version 2.2019 states the following: The panel believes EPI can be considered as an option for men contemplating initial or repeat biopsy. The evidence is sufficient to determine the technology results in a meaningful improvement in net health outcome as indicated by the NCCN panel recommendation.

 

Mi-Prostate Score (MiPS)

The Mi-Prostate score (MiPS) assay measures total serum PSA and post-DRE urine expression of the T2-ERG fusion (TMPRSS2: ERG) as well as another marker, PCA3. The test also predicts risk for having an aggressive tumor, helping doctors and patients make decisions about whether to wait and monitor test levels or pursue immediate biopsy.

 

In a validation study Sanda et. al. (2017) evaluated the priori primary hypothesis that combined measurement of PCA3 and TMPRSS2:ERG (T2;ERG) RNA in the urine after digital rectal exam (DRE) would improve specificity over measurement of prostate specific antigen alone for detecting cancer with Gleason score of 7 or higher. As a secondary objective, to evaluate the potential effect of such urine RNA testing on health care costs. Prospective, multicenter diagnostic evaluation and validation in academic and community based ambulatory urology clinics. Participants were a referred sample of men presenting for first-time prostate biopsy without pre-existing prostate cancer: 516 eligible participants from among 748 cohort participants in the developmental cohort and 561 eligible participants from 928 in the validation cohort. Urinary PCA3 and T2:ERG RNA measurements were taken before the prostate biopsy. The main outcome and measures, presence of prostate cancer having a Gleason score 7 or higher on prostate biopsy. Pathology testing was blinded to urine assay results. In the developmental cohort, a multiplex decision algorithm was constructed using urine RNA assays to optimize specificity while maintaining 95% sensitivity for predicting aggressive prostate cancer at initial biopsy. Findings were validated in a separate multicenter cohort via prespecified analysis, blinded per prospective-specimen-collection, retrospective-blinded-evaluation (PRoBE) criteria. Cost effects of the urinary testing strategy were evaluated by modeling observed biopsy results and previously reported treatment outcomes. Among the 516 men in the developmental cohort (mean age, 62 years; range, 33-85 years) combining testing of urinary T2:ERG and PCA3 at thresholds that preserved 95% sensitivity for detecting aggressive prostate cancer improved specificity from 18% to 39%. Among the 561 men in the validation cohort (mean age, 62 years; range, 27-86 years), analysis confirmed improvement in specificity (from 17% to 33%; lower bound of 1-sided 95% CI, 0.73%; prespecified 1-sided P = .04), while high sensitivity (93%) was preserved for aggressive prostate cancer detection. Forty-two percent of unnecessary prostate biopsies would have been averted by using the urine assay results to select men for biopsy. Cost analysis suggested that this urinary testing algorithm to restrict prostate biopsy has greater potential cost-benefit in younger men.

 

NCCN Guideline Version 2.2019 Prostate Cancer Early Detection, includes the following regarding this test: Given the lack of validation of the models/algorithms in independent publications, the unclear behavior in other screened populations, and the lack of clarity regarding the incremental value and cost effectiveness of this assay, the panel cannot recommended the routine use of this test at this time. Longer term follow-up of the cohorts to determine whether missed prostate cancers were ultimately detected is needed. In addition, validation of these tests in other cohorts of men is needed before they can be accepted as alternatives to (or perhaps preferable to) other tests. The NCCN Panel considers Mi-Prostate score (MiPS) to be investigational at the present time.

 

Summary

There is no direct evidence that supports the clinical utility of the test, and the chain of evidence is incomplete due to the limitations in clinical validity and clinical utility. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

SelectMDx

SelectMDx helps identify patients at increased risk for aggressive disease, thereby aiding in the selection of men for prostate biopsy. SelectMDx for Prostate Cancer is a reverse transcription PCR (RT-PCR) assay performed on post-DRE (digital rectal examination), first void urine specimen from patients with clinical risk factors for prostate cancer, who are being considered for biopsy. The test measures the mRNA levels of the DLX1 and HOXC6 biomarkers, using KLK3 expression as internal reference, to aid in patient selection for prostate biopsy. Higher expression levels of DLX1 and HOXC6 mRNA are associated with an increased probability for high grade (Gleason Score (GS) ≥ 7) prostate cancer.

 

The assay was developed on an initial training set of 519 patients from 2 prospective multicenter studies and was then validated in a separate set of 386 patients from these trials. Using the expression of DLX1 and HOXC6 alone resulted in an AUC of 0.76, a sensitivity of 91%, a specificity of 36%, an NPV of 94%, and a PPV of 27% for the prediction of Gleason score ≥ 7 prostate cancer. When combined with PSA levels, PSAD, DRE results, age and family history in a multimodal model, the overall area under the curve (AUC) was 0.90 in the training set and 0.86 (95% CI, 0.80-0.92) in the validation set. A retrospective observational study compared results of SelectMDx with mpMRI (multi-parametric MRI) results in 172 patients who had mpMRI because of persistent clinical suspicion of prostate cancer or for local staging after positive biopsy. The AUC of SelectMDx for the prediction of mpMRI outcome was 0.83, whereas the AUC for PSA and PCA2 were 0.66 and 0.65, respectively.

 

NCCN Guideline Version 2.2019 Prostate Cancer Early Detection, includes the following regarding this test: Given the lack of validation of the models/algorithms in independent publications, the unclear behavior in other screened populations, and the lack of clarity regarding the incremental value and cost effectiveness of this assay, the panel cannot recommended the routine use of this test at this time. Longer term follow-up of the cohorts to determine whether missed prostate cancers were ultimately detected is needed. In addition, validation of these tests in other cohorts of men is needed before they can be accepted as alternatives to (or perhaps preferable to) other tests. The NCCN Panel considers SelectMDx to be investigational at the present time.

 

Summary

There is no direct evidence that supports the clinical utility of the test, and the chain of evidence is incomplete due to the limitations in clinical validity and clinical utility. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

Genetic and Biomarker Testing for Selection of Men for Repeat Prostate Biopsy

Clinical Context and Test Purpose

The purpose of genetic and protein biomarker testing for prostate cancer is to inform the selection of men who should undergo repeat biopsy. The conventional decision-making tools for identifying men for prostate biopsy include DRE, serum PSA, and patient risk factors such as age, race, and family history of prostate cancer are previously described in the section for selection of men for initial prostate biopsy.

 

Given the risk, discomfort, burden of biopsy, and the low diagnostic yield, there is a need for noninvasive tests that distinguish potentially aggressive tumors that should be referred for rebiopsy from clinically insignificant localized tumors or other prostatic conditions that do not need rebiopsy with the goal of avoiding low-yield biopsy.

 

Patients

The relevant populations are men for whom a rebiopsy is being considered because the results of an initial prostate biopsy were negative or equivocal and other clinical symptoms remain suspicious.

 

Comparators

Standard clinical examination for determining who goes to biopsy might include DRE, review of history of PSA values, along with consideration of risk factors such as age, race, and family history. The ratio of free (unbound) PSA to total PSA is lower in men who have prostate cancer than in those who do not. A percent free PSA (%fPSA) cutoff of 25% has been shown to have a sensitivity and specificity of 95% and 20%, respectively, for a group of men with total PSA levels between 4.0 ng/mL and 10.0 ng/mL.

 

The best way to combine all of the risk information to determine who should go to biopsy is not standardized. Risk algorithms have been developed that incorporate clinical risk factors into a risk score or probability. Two examples are the Prostate Cancer Prevention Trial (PCPT) predictive model and the Rotterdam Prostate Cancer risk calculator (also known as the European Research Screening Prostate Cancer Risk Calculator 4 (ERSPC-RC). The AUA and the Society of Abdominal Radiology recently recommended that high-quality prostate MRI, if available, should be strongly considered in any patient with a prior negative biopsy who has persistent clinical suspicion for prostate cancer and who is under evaluation for a possible repeat biopsy.

 

Outcomes

The beneficial outcome of the test is to avoid a negative biopsy for prostate cancer. A harmful outcome is failure to undergo a biopsy that would be positive for prostate cancer, especially when disease is advanced or aggressive. Thus the relevant measures of clinical validity are the sensitivity and negative predictive value. The appropriate reference standard is biopsy, though prostate biopsy is an imperfect diagnostic tool. Biopsies can miss cancers and repeat biopsies are sometimes needed to confirm the diagnosis. Detection rates vary by biopsy method and patient characteristics, with published estimates between 10% and 28% for a second biopsy and 5% and 10% for a third biopsy.

 

Timing

The timeframe of interest for calculating performance characteristics is time to biopsy result. Men who forgo biopsy based on test results could miss or delay diagnosis of cancer. Longer follow-up would be necessary to determine effects on overall survival.

 

Setting

Screening using PSA levels and DRE may be performed in the primary care setting with referral to specialty (urologist) care for suspicious findings and biopsy. Clinical practice on screening methods and frequency vary widely.

 

Progensa PCA3 Assay

Progensa PCA3 Assay (prostate cancer gene 3) is overexpressed in prostate cancer, this test measures the concentration of PCA3 mRNA and prostate-specific antigen (PSA) and calculates a ratio of PCA3 molecules to PSA molecules (PCA3 Score) in post-digital rectal exam (DRE) first catch urine specimen. Progensa PCA3 Assay is indicated for use in conjunction with other risk indicators to aid in patient management in the “at risk” population of men 50 years of age or older who have had 1 or more previous negative prostate biopsies and for whom a repeat biopsy would be recommended by a urologist based on the current standard of care.

 

The Progensa PCA3 assay (Hologic Gen-Probe) has been approved by the FDA to aid in the decision for repeat biopsy in men 50 years or older who have had 1 or more negative prostate biopsies and for whom a repeat biopsy would be recommended based on current standard of care. The Progensa PCA3 assay should not be used for men with atypical small acinar proliferation (ASAP) on their most recent biopsy.

 

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

 

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome of care can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary testing.

 

Based on National Comprehensive Cancer Network (NCCN) guideline Prostate Early Detection Version 2.2019, when a patient meets the standards for biopsy, sometimes the patient and physicians wish to further define the probability of cancer before proceeding to biopsy with its associated risks. Several biomarker tests have been developed with the goals of refining patient selection for biopsies, decreasing unnecessary biopsies, and increasing the specificity of cancer detection, without missing a substantial number of higher grade (Grade Group ≥ 2) cancers. These tests may be especially useful in men with PSA levels between 3 and 10 ng/mL. Most often, these tests have been used in patients who have had one negative biopsy to determine if repeat biopsy is an appropriate consideration. NCCN also notes that biomarkers that improve the specificity of detection are not recommended as first-line screening tests, rather for use in those individuals who wish to further define the probability of high-grade cancer.

 

Based on the NCCN 2A recommendation, the NCCN panel recommends that PCA3 may be considered for men who have had a least one prior negative biopsy and are thought to be at a higher risk for clinically significant prostate cancer.

 

In a prospective multicenter clinical study of 466 men with at least 1 prior negative prostate biopsy, a PCA3 score cutoff of 25 showed a sensitivity of 78%, specificity of 57%, negative predictive value (NPV) of 90%,and PPV of 34%. Men with a score of ≥ 25 were 4.6 times more likely to have a positive repeat biopsy than those with a score < 25.

Results were reported from an NCI Early Detection Research Network (EDRN) validation study of the PCA3 urinary assay in 859 men scheduled for a diagnostic prostate biopsy in 11 centers. The primary outcomes reported at a PPV of 80% (95% CI, 72%-86%) in the initial biopsy setting and NPV of 88% (95% CI, 81%-93%) in the repeat biopsy setting. Based on the data, use of PCA3 in the repeat biopsy setting would reduce the number of biopsies by almost half, and 3% of men with a low PCA3 score would have high grade prostate cancer that would be missed. In contrast, the risk of high-grade disease in men without prior biopsy with a low PCA3 is 13%. Thus, the NCCN panel believes that this test is not appropriate to use in the initial biopsy setting.

 

Summary

The use of Progensa PCA3 (prostate cancer gene 3) biomarker test is supported by published professional society guideline – National Comprehensive Cancer Network (NCCN) Prostate Cancer Early Detection 2.2019 as a 2A recommendation. When a patient meets the standards for biopsy, sometimes the patient and physicians wish to further define the probability of cancer before proceeding to biopsy with its associated risks. Several biomarker tests have been developed with the goals of refining patient selection for biopsies, decreasing unnecessary biopsies, and increasing the specificity of cancer detection, without missing a substantial number of higher grade (Grade Group ≥ 2) cancers. These tests may be especially useful in men with PSA levels between 3 and 10 ng/mL. Most often, these tests have been used in patients who have had one negative biopsy to determine if repeat biopsy is an appropriate consideration. NCCN also notes that biomarkers that improve the specificity of detection are not recommended as first-line screening tests, rather for use in those individuals who wish to further define the probability of high-grade cancer. The NCCN panel recommends the Progensa PCA3 Assay (prostate cancer gene 3) as an option in men being considered for repeat biopsy after an initially benign result. The evidence is sufficient to determine the technology results in a meaningful improvement in net health outcome as indicated by the NCCN panel recommendation.

 

ConfirmMDx

Gene Hypermethylation

One of the epigenetic mechanisms that is considered to be involved in the development of prostate cancer is DNA methylation. Hypermethylation within promotor region of tumor suppressor genes is an important mechanism of gene inactivation and has been described for many different tumor types. These types of alterations are also potentially reversible, unlike genetic alterations such as mutations, which may lead them being considered as possible targets for gene therapy. Currently, aberrant promoter hypermethylation has been investigated in specific genes from the following groups: tumor-suppressor genes, proto-oncogenes, genes involved in cell adhesion, and genes involved in cell-cycle regulation. Glutathione S-transferase P1 (GSTP1) is the most widely studied methylation markers for prostate cancer, usually as a diagnostic application. Several studies reported associations between DNA hypermethylation at various gen loci (RASSF1A, APC, GSTP1, PTGS2, RQQR-beta, TIG1, AOX1, C1orf114, GAS6, HAPLN3, KLF8, MOB3B) and prostate cancer. It has been suggested that a valuable first step in diagnostic use might be to test for methylated genes to select patients undergoing prostate biopsy who might not require a repeat biopsy.

 

In a 2012 meta-analysis by Van Neste et. al., 30 peer-reviewed studies of hypermethylation of GSTP1 and other genes in prostate tissue were evaluated.88 The pooled estimates of sensitivity for GSTP1 to distinguish prostate cancer from normal in biopsies (328 cases, 263 controls) was 82%, with 95% specificity, 95% NPV (negative predictive value), and 85% PPV (positive predictive value). The combination of GSTP1, APC, and RARβ had a sensitivity of 95%, specificity of 95%, NPV of 99%, and PPV of 95%. Reviewers suggested that a valuable first step in diagnostic use might be to test for methylated genes to select patients undergoing prostate biopsy who might not require repeat biopsy.

 

Following the 2012 meta-analysis, several studies reported on associations between DNA hypermethylation at various gene loci (RASSF1A, APC, GSTP1, PTGS2, RARβ, TIG1, AOX1, C1orf114, GAS6, HAPLN3, KLF8, MOB3B) and prostate cancer.

 

ConfirmMDx (MDxHealth)

ConfirmMDx measures the methylation levels using quantitative methylation PCR of 3 genes (GSTP1, APC, RASSF1) associated with prostate cancer. ConfirmMDx is intended for use in patients with high-risk factors such as elevated/rising prostate specific antigen (PSA) or abnormal digital rectal examination (DRE), with a negative or non-malignant abnormal histopathology finding (e.g. atypical cell or high grade prostate intraepithelial neoplasia [HGPIN]) in the previous biopsy, and is being considered for repeat biopsy. Several case/controls tudies in archived biopsy core tissue blocks demonstrated the sensitivity, specificity and high negative predictive value (NPV) of this biomarker to predict cancer detection in a repeat biopsy procedure. Single biopsy cores, using a little as 20 microns from formalin-fixed, paraffin embedded (FFPE) tissue blocks or sections cut from blocks fixed on glass slides are used in this assay.

 

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

 

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome of care can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary testing.

 

Based on National Comprehensive Cancer Network (NCCN) guideline Prostate Early Detection Version 2.2019, when a patient meets the standards for biopsy, sometimes the patient and physicians wish to further define the probability of cancer before proceeding to biopsy with its associated risks. Several biomarker tests have been developed with the goals of refining patient selection for biopsies, decreasing unnecessary biopsies, and increasing the specificity of cancer detection, without missing a substantial number of higher grade (Grade Group ≥ 2) cancers. These tests may be especially useful in men with PSA levels between 3 and 10 ng/mL. Most often, these tests have been used in patients who have had one negative biopsy to determine if repeat biopsy is an appropriate consideration. NCCN also notes that biomarkers that improve the specificity of detection are not recommended as first-line screening tests, rather for use in those individuals who wish to further define the probability of high-grade cancer.

 

Based on the NCCN 2A recommendation, the NCCN panel recommends that ConfirmMDx can be considered for men who have had at least one prior negative biopsy and are thought to be at higher risk for clinically significant prostate cancer.

 

The European MATLOC study blindly tested this assay in archived tissue from 498 men with negative biopsies who had repeat biopsies within 30 months. The NPV was 90% (95% CI, 87%-93%). In multivariate analysis, ConfirmMDx was predictive of patient outcome (OR, 3.17; 95% CI, 1.81-5.53). A similar validation study was performed in the United States using archived tissue from 350 men when negative biopsies who had repeat biopsies within 24 months. The NPV was 83% (95% CI, 85%-91%), and the test was again found to be predictive of outcomes on multivariate analysis (OR, 2.69; 95% CI, 1.60-4.51).

 

Summary

The use of ConfirmMDx biomarker test is supported by published professional society guideline – National Comprehensive Cancer Network (NCCN) Prostate Cancer Early Detection 2.2019 as a 2A recommendation. When a patient meets the standards for biopsy, sometimes the patient and physicians wish to further define the probability of cancer before proceeding to biopsy with its associated risks. Several biomarker tests have been developed with the goals of refining patient selection for biopsies, decreasing unnecessary biopsies, and increasing the specificity of cancer detection, without missing a substantial number of higher grade (Grade Group ≥ 2) cancers. These tests may be especially useful in men with PSA levels between 3 and 10 ng/mL. Most often, these tests have been used in patients who have had one negative biopsy to determine if repeat biopsy is an appropriate consideration. NCCN also notes that biomarkers that improve the specificity of detection are not recommended as first-line screening tests, rather for use in those individuals who wish to further define the probability of high-grade cancer. The NCCN panel recommends the ConfirmMDx test can be considered for men who have had at least one prior negative biopsy and are thought to be at high risk. The evidence is sufficient to determine the technology results in a meaningful improvement in net health outcome as indicated by the NCCN panel recommendation.

 

4KScore

The 4Kscore test (OPKO Lab) is a blood test that generates a risk score estimating the probability of finding high-grade prostate cancer (defined as a Gleason Score > 7) if a prostate biopsy were performed. The intended use of the test is to aid in the decision of whether or not to proceed with a prostate biopsy or repeat prostate biopsy. A kallikrein is a subgroup of enzymes that cleaves peptide bonds in proteins. The intact prostate-specific antigen (iPSA) and human kallikrein 2 (hK2) tests are immunoassays that employ distinct mouse monoclonal antibodies. The score combines the measurement of 4 prostate-specific kallikreins (total prostate specific antigen (tPSA), free PSA (fPSA), intact PSA (iPSA), and human kallikrein 2 (hK2)), with an algorithm including patient age, digital rectal exam (DRE), and prior prostate biopsy history.

 

The manufacturer’s website states that the ideal patient for the 4Kscrore is one whose other test results are equivocal. The test is not intended for patients with a previous diagnosis of prostate cancer, who have had a digital rectal examination (DRE) in the previous 4 days of this test, who have received 5-alpha reductase inhibitor therapy in the previous 6 months (such as Avodart [dutasteride] or Proscar [finasteride]), or has undergone within the previous 6 months any procedure or therapy to treat symptomatic benign prostatic hypertrophy (BPH) or any invasive urologic procedure that may be associated with a secondary PSA elevation.

 

Based on the 4Kscore Test U.S. validation study, prostate biopsy should be considered in most men with a 4kscore result of 7.5% or higher. Reference ranges are as follows:

  • Low risk: 4Kscore result < 7.5%
  • Intermediate Risk: 4Kscore result 7.5%-19%
  • High Risk: 4Kscore result ≥ 20%

 

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

 

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome of care can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary testing.

 

Based on National Comprehensive Cancer Network (NCCN) guideline Prostate Early Detection Version 2.2019, when a patient meets the standards for biopsy, sometimes the patients and physicians wish to further define the probability of cancer before proceeding to biopsy with its associated risks. Several biomarker tests have been developed with the goals of refining patient selection for biopsies, decreasing unnecessary biopsies, and increasing the specificity of cancer detection, without missing a substantial number of higher grade (Grade Group ≥ 2) cancers. These tests may be especially useful in men with PSA levels between 3 and 10 ng/mL. NCCN also notes that biomarkers that improve the specificity of detection are not recommended as first-line screening tests, rather for use in those individuals who wish to further define the probability of high-grade cancer.

 

Based on the NCCN 2A recommendation, the NCCN panel consensus is that the 4Kscore test can be considered for patients prior to biopsy and for those with prior negative biopsy who are thought to be at higher risk for clinically significant prostate cancer.

 

A prospective multi-institutional U.S. trial of 1012 patients showed that 4Kscore results have a high discrimination value (area under the curve (AUC), 0.82). In this study, using a threshold biopsy of ≥ 15% risk allowed for 591 biopsies to be avoided (58%), while 183 high-grade tumors were detected and 48 high grade tumors (4.7% of the 1012 participants) were missed. When 4Kscore was examined in 6129 men in another prospective study, the AUC was also 0.82 (95% CI, 0.80-0.84). Using a 6% risk of high-grade cancer cutoff, 428 of 1000 men could avoid biopsy, with 119 of 133 high grade cancers detected and 14 of 133 missed. A multi-center clinical utility study found a 65% reduction in prostate biopsies with use of 4Kscore test. In addition, a correlation between 4Kscore risk category and Gleason score was seen (P < .01). A meta-analysis that included 12 clinical validation studies (11,134 patients) led to a calculated pooled AUC for discrimination of prostate cancer with Gleason score of ≥ 7 of 0.81 (fixed effects 95% CI, 0.80-0.83).

 

Summary

The use of 4Kscore biomarker test is supported by published professional society guideline – National Comprehensive Cancer Network (NCCN) Prostate Cancer Early Detection 2.2019 as a 2A recommendation. When a patient meets the standards for biopsy, sometimes the patient and physicians wish to further define the probability of cancer before proceeding to biopsy with its associated risks. Several biomarker tests have been developed with the goals of refining patient selection for biopsies, decreasing unnecessary biopsies, and increasing the specificity of cancer detection, without missing a substantial number of higher grade (Grade Group ≥ 2) cancers. These tests may be especially useful in men with PSA levels between 3 and 10 ng/mL. NCCN also notes that biomarkers that improve the specificity of detection are not recommended as first-line screening tests, rather for use in those individuals who wish to further define the probability of high-grade cancer. The NCCN panel consensus is that the 4Kscore test can be considered for patients prior to biopsy and for those with prior negative biopsy who are thought to be at higher risk for clinically significant prostate cancer. The evidence is sufficient to determine the technology results in a meaningful improvement in net health outcome as indicated by the NCCN panel consensus.

 

TMPRSS Fusion Genes and Mi-Prostate Score (MiPS)

TMPRSS2 is an androgen-regulated transmembrane serine protease that is preferentially expressed in normal prostate tissue. In prostate cancer, it may be fused to an ETS (E26 transformation-specific) family transcription factor (ERG, ETV1, ETV4, or ETV5), which modulates transcription of target genes involved in cell growth, transformation and apoptosis. The result of gene fusion with an ETS transcription gene is that the androgen-responsive promoter of TMPRSS2 upregulates expression of the ETS gene, suggesting a mechanism for neoplastic transformation. Fusion genes may be detected in tissue, serum and urine.

 

TMPRSS2-ERG gene rearrangements have been reported in 50% or more of primary prostate cancer samples. Although ERG appears to be the most common ETS family transcription factor involved in the development of fusion genes, not all are associated with TIMPRSS2. About 6% of observed rearrangements are seen with SLC45A3, and about 5% appear to involve other types of rearrangement. Attention has been directed at using post-DRE urine samples to look for fusion genes as markers of prostate cancer.

 

In 2014, Yao et. al. published a systematic review with meta-analysis of TMPRSS2-ERG for the detection of prostate cancer. Literature was searched through July 2013, and 32 articles were included. Pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were 47% (95% CI, 46% to 49%), 93% (95% CI, 92% to 94%), 8.9 (95% CI, 5.7 to 14.1), and 0.49 (95% CI, 0.43 to 0.55), respectively. Statistical heterogeneity was high (I2>85%). It was unclear whether studies in screening populations were pooled with enriched patient samples (e.g., elevated PSA and/or negative biopsy). There also was variability in the type of tissue samples analyzed (urine, prostatic secretions, biopsy, surgical specimens); the type of TMPRSS2-ERG assays used (fluorescence in situ hybridization, immunohistochemistry, real-time reverse transcriptase PCR, transcription-mediated amplification); and in TMPRSS2-ERG threshold cutoff values.

 

Mi-Prostate Score (MiPS)

As described above under testing for initial prostate biopsy, Mi-Prostate Score (MiPS) can also be utilized in individuals who had prior negative biopsy, to determine if repeat biopsy should be performed.

 

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

 

Tomlins et. al. (2011) developed a transcription-mediated amplification assay to measure TMPRSS2-ERG fusion transcripts in parallel with PCA3. Combining results from the TMPRSS2-ERG and PCA tests and incorporating them into the multivariate PCPT risk calculator appeared to improve identification of patients with clinically significant cancer using Epstein criteria and high-grade cancer on biopsy. Although the study was large (1312 men at multiple centers), it was confounded by assay modifications during the study and by use of cross-validation rather than independent validation, using independent training and testing sets.

 

In 2013, this same group evaluated 45 men using a multivariable algorithm that included serum PSA plus urine TMPSS2-ERG and PCA3 from a post-DRE sample. Samples were collected before prostate biopsy at 2 centers. For cancer prediction, sensitivity and specificity were 80% and 90%, respectively. Area under the curve (AUC) was 0.88.

 

In 2016, Tomlins et. al. published results of a validation study of the MiPS score in 1244 prospectively collected, post-DRE urine samples from 7 U.S. clinics. A total of 1225 of the specimens had sufficient materials for both TMPSS2-ERG and PCA3 analysis and were included. Eighty percent of patients were presenting for initial biopsy. Seventy-three percent were white; the percentage of African Americans was not given. Approximately 25% of the men were older than 70. Twenty-three percent had an abnormal DRE, and the median PSA level was 4.7 ng/mL. The AUCs for predicting any cancer using PSA alone, PCPT risk calculator alone, and the MiPS score alone were 0.59, 0.64, and 0.76, respectively (CIs not given, p<0.001 for MiPS vs PCPT). The area under the curve (AUCs) for predicting high-grade cancer were 0.65, 0.71, and 0.78, respectively (p<0.001 for MiPS vs PCPT). A MiPS score threshold for recommending biopsy has not been provided, and so sensitivity and NPV (negative predictive value) were not calculated.

 

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome of care can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary testing.

 

Tomlins et. al. (2016) also used decision-curve analysis to estimate the number of biopsies that would have been performed and cancers that would have been missed using a MiPS risk cutoff for biopsy in their cohort. Compared with a biopsy-all strategy, using a MiPS cutoff for aggressive cancer of 15% would have avoided 36% of biopsies while missing 7.0% of any prostate cancer and 1.6% of high-grade prostate cancer diagnoses. Using the PCPT risk calculator cutoff of 15% for aggressive cancer would have avoided 68% of biopsies while missing 25% of any cancer and 8% of high-grade cancer.

 

No studies were found that directly show the effects of using MiPS results on clinical outcomes. Given the lack of direct evidence of utility, a chain of evidence would be needed to demonstrate clinical utility. The MiPS test is associated with a diagnosis of prostate cancer and aggressive prostate cancer. The clinical validity study of the MiPS test included men with relevant PSA levels but also included men with positive DRE who would not likely forgo biopsy. The clinical validation study included comparison of performance characteristics with standard risk calculators; comparison with percent free PSA was not provided. Confirmation of performance characteristics is needed. No prospective data are available on using the MiPS score for decision making. No data are available on the longer term clinical outcomes of the men who did not have biopsy based on MiPS results. The chain is incomplete.

 

NCCN Guideline Version 2.2019 Prostate Early Detection, includes the following regarding this test: Given the lack of validation of the models/algorithms in independent publications, the unclear behavior in other screened populations, and the lack of clarity regarding the incremental value and cost effectiveness of this assay, the panel cannot recommended the routine use of this test at this time. Longer term follow-up of the cohorts to determine whether missed prostate cancers were ultimately detected is needed. In addition, validation of these tests in other cohorts of men is needed before they can be accepted as alternatives to (or perhaps preferable to) other tests. The NCCN Panel considers Mi-Prostate score (MiPS) to be investigational at the present time.

 

Summary

Concomitant detection of TMPRSS2:ERG and PCA3 may more accurately identify geno typical men with prostate cancer. However, current evidence is insufficient to support its use. Estimated accuracy varies across available studies. The Mi-Prostate Score (MiPS) test has preliminary data suggesting improved clinical validity compared to the PCPT risk calculator in a validation study but independent confirmation of clinical validity and comparison with percent free PSA (%fPSA) is needed. Data on clinical utility is lacking. NCCN Guideline Version 2.2019 Prostate Early Detection, includes the following regarding this test: Given the lack of validation of the models/algorithms in independent publications, the unclear behavior in other screened populations, and the lack of clarity regarding the incremental value and cost effectiveness of this assay, the panel cannot recommended the routine use of this test at this time. Longer term follow-up of the cohorts to determine whether missed prostate cancers were ultimately detected is needed. In addition, validation of these tests in other cohorts of men is needed before they can be accepted as alternatives to (or perhaps preferable to) other tests. The NCCN Panel considers Mi-Prostate score (MiPS) to be investigational at the present time. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

Prostate Core Mitomics Test

The Prostate Core Mitomics Test (PCMT; Mitomics; formerly Genesis Genomics) is a proprietary test that is intended to determine whether a patient has prostate cancer, despite a negative prostate biopsy, by analyzing deletions in the mitochondrial DNA by polymerase chain reaction (PCR) to detect “tumor field effect.” The test is performed on the initial negative prostate biopsy tissue. According to the company website, a negative PCMT result confirms the results of the negative biopsy (i.e. the patient does not have prostate cancer) and the patient can avoid a second biopsy, but a positive PCMT means the patient is at high risk of undiagnosed prostate cancer. The website also states that physicians should consider using PCMT for patients who have a negative initial biopsy but continue to have elevated PSA, rising PSA, irregular DRE, atypical small acinar proliferation, high-grade prostatic intraepithelial neoplasia or inconclusive biopsy.

 

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

 

A 2006 study retrospectively analyzed mitochondrial DNA variants from 3 tissue types from 24 prostatectomy specimens: prostate cancer, adjacent benign tissue, and benign tissue distant to the tumor (defined as tissue from a non-diseased lobe or at least 10-cell diameters from the tumor if in the same lobe). Prostate needle biopsy tissue (from 12 individuals referred for biopsy) that were histologically benign were used as controls. Results from the prostatectomy tissue analysis showed that 16 (66.7%) of 24 had variants in all 3 tissue types, 22 (91.7%) of 24 had variants in malignant samples, 19 (79.2%) of 24 in adjacent benign samples, and 22 of 24 in distant benign glands. Overall, 273 somatic variants were observed in this sample set. In the control group, 7 (58.3%) patients had between 1 and 5 genetic alterations, mainly in noncoding regions. The authors concluded that the variants found in the malignant group vs the control group differed significantly and that mitochondrial DNA variants are an indicator of malignant transformation in prostate tissue.

 

In 2008, Maki et.al. reported on the discovery and characterization of a 3.4-kilobase mitochondrial genome deletion and its association with prostate cancer. A pilot study analyzed 38 benign biopsy specimens from 22 patients, 41 malignant biopsy specimens from 24 patients, and 29 proximal to malignant (PTM) biopsy specimens from 22 patients. All patients with malignant biopsies had a subsequent prostatectomy, and the diagnosis of cancer was confirmed. The PTM biopsy samples were negative for cancer and were from the cohort that underwent prostatectomy. A confirmation study used 98 benign biopsy specimens from 22 patients, 75 malignant biopsy specimens from 65 patients, and 123 PTM biopsy specimens from 96 patients. In the confirmation study, patients had to have at least 2 successive negative biopsies; the first negative biopsy was used for analyses. For both the pilot and confirmation studies, samples for analysis were selected based on a review of pathology reports. The levels of the variation were measured by quantitative PCR and, based on PCR cycle threshold, data were used to calculate a score for each biopsy sample. In the pilot study, the scores were statistically significant between benign and malignant (p<0.000) and benign and proximal (p<0.003) samples. The PTM samples closely resembled the malignant sample, with no statistically significant resolution between the scores (p<0.833), to which the authors attributed to a field cancerization phenomenon. Results from the larger confirmation study were similar. Compared with histopathologic examination of the benign and malignant samples, the sensitivity and specificity were 80% and 71%, respectively, and the area under the receiver operating characteristics (AUROC) was 0.83 for the deletion. A blinded, external validation study showed a sensitivity and specificity of 83% and 79% and the AUROC of 0.87.

 

In 2010, Robinson et. al. assessed the clinical value of the 3.4 kilobase deletion described in the Maki study in predicting rebiopsy outcomes. Levels of the deletion were measured by quantitative PCR in prostate biopsies negative for cancer from 101 patients who underwent repeat biopsy within 1 year and had known outcomes. Of the 101 first biopsies, the diagnosis was normal in 8, atypical and/or had prostatic intraepithelial neoplasia in 50, and hyperplasia or inflammation in 43. The clinical performance of the deletion was calculated with the use of an empirically established cycle threshold cutoff, the lowest cycle threshold as diagnostic of prostate cancer, and the histopathologic diagnosis on second biopsy. Final data were based on 94 patients, who on second biopsy had 20 malignant and 74 benign diagnoses.

 

The cycle cutoff gave a sensitivity and specificity of 84% and 54%, respectively, with an AUROC of 0.75. NPV was 91%.

 

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome of care can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary testing.

 

No peer-reviewed, full-length publications on the clinical utility of the commercially available Prostate Core Mitomics Test (PCMT) was identified.

 

Summary

The Prostate Core Mitomics Test (PCMT) has preliminary data on performance characteristics in small validation study but independent confirmation of clinical validity is needed. The studies did not provide estimates of validity compared to a standard clinical examination. No data is available on long term clinical outcomes. Data on clinical utility is lacking. NCCN guideline 2.2019 Prostate Cancer Early Detection, does not discuss or indicate the use of the Prostate Core Mitomics Test (PCMT) within this guideline. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

Expanded Gene Panels and Single-Nucleotide Variant Testing

Since no single gene markers have been found that are both highly sensitive and highly specific for diagnosing prostate cancer, particularly in geno typical men already known to have an elevated PSA level, some investigators are combining several promising markers into a single diagnostic gene panel. Although promising in concept, only single studies of various panels have been published.

 

Single nucleotide Variants (SNVs) occur when a single nucleotide is replaced with another, and they are the most common type of genetic variation in humans. They occur normally throughout the genome and can act as biological markers for disease association. Genome-wide association studies have identified associations between prostate cancer risk and specific SNVs. However, it is widely accepted that individually, SNV-associated disease risk is low and of no value in screening for disease, although multiple SNVs in combination may account for a higher proportion of prostate cancer. Investigators have begun to explore the use of algorithms incorporating information from multiple SNVs to increase the clinical value of testing.

 

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

 

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome of care can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary testing.

 

Ma et. al. (2014) examined various algorithms for cancer diagnosis and prognosis using urine and plasma levels of multiple genes, including PCA3, PSA, TMPRSS2, and ERG. One algorithm distinguished prostate cancer from benign prostatic hypertrophy with an AUC of 0.78. Another algorithm distinguished men with a Gleason score 7 or higher for men with a Gleason score less than 7 (AUC=0.88). Combination of these 2 algorithms into a scoring system predicted the presence of a Gleason score 7 or higher in 75% of men. Qu et al (2013) reported on preliminary results of a 3-gene panel (androgen receptor [AR], PTEN, TMPRSS2-ERG) analyzed by fluorescence in situ hybridization.112 Thirty-one percent of 110 archived primary tumor samples and 97 metastatic tumor samples from a separate cohort of patients were analyzable. Chromosomal abnormalities were detected in 53% of primary prostate cancers and in 87% of metastatic tumors (p<0.001).

 

In 2015, Leyten et. al. reported on the development of a gene panel using specimens from 133 patients that included 3 urinary biomarkers (HOXC6, TDRD1, DLX1). When the gene panel was used with PSA, the combined AUC for predicting high-grade prostate cancer was 0.81 (95% CI, 0.75 to 0.86), which was higher than the concurrently measured Progensa AUC of 0.68 (95% CI, 0.62 to 0.75). Xiao et al (2016) reported the development of an 8-gene panel (PMP22, HPN, LMTK2, FN1, EZH2, GOLM1, PCA3, GSTP1) that was able to distinguish high-grade prostate cancer from indolent prostate cancer with a sensitivity of 93% (95% CI, 88% to 97%), a specificity of 70% (95% CI, 36% to 104%), a PPV of 98% (95% CI, 95% to 100%), and an NPV of 61% (95% CI, 25% to 97%) in a specimen cohort of 158 men.

 

A 2012 Agency for Healthcare Research and Quality report on multigene panels in prostate cancer risk assessment reviewed the literature on SNV panel tests for assessing risk of prostate cancer. All of the studies included in the review had poor discriminative ability for predicting risk of prostate cancer, had moderate risk of bias, and none of the panels had been evaluated in routine clinical settings. The conclusions of the review were that the evidence on currently available SNV panels does not permit meaningful assessment of analytic validity, the limited evidence on clinical validity is insufficient to conclude that SNV panels would perform adequately as a screening test and that there is no evidence available on the clinical utility of current panels.

 

Kader et. al. (2012) evaluated a panel of 33 prostate cancer‒associated SNVs identified from genome-wide association studies in 1654 men. Genetic score was a significant (p<0.001) independent predictor of prostate cancer (OR=1.72; 95% CI, 1.44 to 2.09) after adjusting for clinical variables and family history. Addition of genetic markers to the classification of prostate cancer risk resulted in 33% of men by reclassified into a different risk quartile. Approximately half of these (n=267) were downgraded to a lower risk quartile, and the other half (n=265) were upgraded into a higher risk quartile. The net reclassification benefit was 10% (p=0.002). The authors concluded that, with the additional information of genetic score, the same number of cancers could be detected but with 15% fewer biopsies.

 

In a 2010 review by Ioannidis et al, 27 gene variants across a large range of chromosomal locations were identified that increased risk for prostate cancer, although, in all cases, the observed incremental risk was modest (OR≤1.36).

 

Lindstrom et. al. (2011), in a study of 10,501 cases of prostate cancer and 10,831 controls, identified 36 SNVs showing association with prostate cancer risk, including two (rs2735893, rs266849) that showed differential association with Gleason score. Per allele odds ranged from 1.07 to 1.44.

 

Ishak and Giri (2011) reviewed 11 replication studies involving 30 SNVs (19 in men of African descent, 10 in men with familial prostate cancer). Odds ratios were positively associated with prostate cancer, although the magnitude of association was small (range, 1.11-2.63).

 

Summary

Numerous studies have demonstrated the association of many gene panels and single nucleotide variants (SNVs) with prostate cancer. These studies, in early stages of development, have generally shown a modest degree of association with future risk for prostate cancer. The clinical utility of these tests is uncertain; there is no evidence that information obtained from gene panels or single nucleotide variants (SNV) testing can be used to change management in ways that improve outcomes. Expanded gene panels that evaluate the likelihood of prostate cancer on biopsy are in development. The NCCN guideline 2.2019 Prostate Cancer Early Detection, does not discuss or indicate the use of the expanded gene panels or single nucleotide variants (SNVs) within this guideline The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

Practice Guidelines and Position Statements

American Urological Association (AUA)

In 2013 (reviewed and validity confirmed 2018), the American Urological Association (AUA) published guidelines for the early detection of prostate cancer:

 

This guideline addresses prostate cancer early detection for the purpose of reducing prostate cancer mortality with the intended user as the urologist. This document does not make a distinction between early detection and screening for prostate cancer. Early detection and screening both imply detection of disease at an early, pre-symptomatic stage when a man would have no reason to seek medical care –an intervention referred to as secondary prevention. In the U.S., early detection is driven by prostate specific antigen (PSA) – based screening followed by prostate biopsy for diagnostic confirmation.

 

While the benefits of PSA-based prostate cancer screening have been evaluated in randomized-controlled trials, the literature supporting the efficacy of DRE, PSA derivatives and isoforms (e.g. free PSA, 2proPSA, prostate health index, hK2, PSA velocity or PSA doubling time) and novel urinary markers and biomarkers (e.g. PCA3) for screening with the goal of reducing prostate cancer mortality provide limited evidence to draw conclusions. While some data suggest use of these secondary screening tools may reduce unnecessary biopsies (i.e reduce harms) while maintain the ability to detect aggressive prostate cancer (i.e. maintain the benefits of PSA screening), more research is needed to confirm this. However, the likelihood of future population-level screening study using these secondary screening approaches is highly unlikely at least in the near future. Therefore, this document focuses only on the efficacy of PSA screening for the early detection of prostate cancer with the specific intent to reduce prostate cancer mortality and not secondary tests often used after screening to determine the need for a prostate biopsy or a repeat prostate biopsy (e.g., PSA isoforms, PCA3, imaging).

 

Guideline Statements:

  • The Panel recommends against PSA screening in men under age 40 years
    • In this age group there is a low prevalence of clinically detectable prostate cancer, no evidence demonstrating benefit of screening and likely the same harms of screening as in other age groups.
  • The Panel does not recommend routine screening in men between ages 40 to 54 years at average risk.
    • For men younger than age 55 years at higher risk, decisions regarding prostate cancer screening should be individualized. Those at higher risk may include men of African American race; and those with a family history of metastatic or lethal adenocarcinomas (e.g. prostate, male and female breast cancer, ovarian and pancreatic) spanning multiple generations, affecting multiple first degree relatives, and that develop at younger ages.
  • For men ages 55 to 69 years the Panel recognizes that the decision to undergo PSA screening involves weighing the benefits of reducing the rate of metastatic prostate cancer and prevention of prostate cancer death against the known potential harms associated with screening and treatment. For this reason, the Panel strongly recommends shared decision-making for men aged 55 to 69 years that are considering PSA screening, and proceeding based on a man’s values and preferences.
    • The greatest benefit of screening appears to be in men ages 55 to 69 years.
    • Multiple approaches subsequent to PSA test (e.g. urinary and serum biomarkers, imaging, risk calculators) are available for identifying men more likely to harbor a prostate cancer and/or one with an aggressive phenotype. The use of such tools can be considered in men with a suspicious PSA level to inform prostate biopsy decisions.
  • To reduce the harms of screening, a routine screening interval of two years or more may be preferred over annual screening in those men who have participated in shared decision making and decided on screening. As compared to annual screening, it is expected that screening intervals of two years preserve the majority of the benefits and reduce over-diagnosis and false positives.
    • Additionally, intervals for rescreening can be individualized by a baseline PSA level.
  • The panel does not recommend routine PSA screening in men over age 70 years or any man with less than 10 to 15 year life expectancy.
    • Some men over age 70 years who are in excellent health may benefit from prostate cancer screening.

 

National Comprehensive Cancer Network (NCCN)

Prostate Cancer Early Detection Version 2.2019
Biomarker Testing: PSA Derivatives and Other Tests

When the first recommendations for early detection programs for prostate cancer were made, serum tPSA was the only PSA-based test available. PSA derivatives and other assays exist that potentially improve the specificity of testing and thus may diminish the probability of unnecessary biopsies.

 

When a patient meets the standards for biopsy, sometimes the patient and physician wish to further define the probability of cancer before proceeding to biopsy with is associated risks. Several biomarker tests have been developed with the goals of refining patient selection for biopsies, decreasing unnecessary biopsies, and increasing the specificity of cancer detection, without missing a substantial number of higher grade (Gleason ≥ 7) cancers. These tests may be especially useful in men with PSA levels between 3 and 10 ng/mL. Most often, these tests have been used in patients who have had negative biopsy to determine if repeat biopsy is an appropriate consideration.

 

The Panel recommends consideration of biomarker tests that have been validated in peer-reviewed, multi-site studies using an independent cohort of patients. These include percent free PSA (%f PSA), Prostate Health Index (PHI) and 4Kscore, or EPI in patients with PSA levels > 3ng/mL who have not yet had a biopsy. Percent free PSA (%fPSA), PHI, 4Kscore, EPI, PCA3 and ConfirmMDx may also be considered for men who have had at least one prior negative biopsy and are thought to be a higher risk. Results of biomarker assays can be complex and should be interpreted with caution. Referral to specialist should be considered. It should be pointed out that multiparametric MRI is also a consideration in these same patients.

 

Head-to-head comparisons have been performed in Europe for some of these tests, used independently or in combinations in the initial or repeat biopsy settings, but sample sizes were small and results varied. Therefore, the panel believes that no biomarker test can be recommended over any other at this time. Furthermore, a biomarker test can be done alone or in addition to multiparametric MRI/refined biopsy techniques. The optimal order of biomarker tests and imaging is unknown; and it remains unclear how to interpret results of multiple tests in individual patients – especially when results are contradictory. Results of any of these tests, when performed, should be included in discussions between clinician and patient to assist in decisions regarding whether to proceed with biopsy.

 

PCA3

PCA3 is a noncoding, prostate tissue specific RNA that is over-expressed in prostate cancer. Current assays quantify PCA3 over-expression in post-DRE urine specimens. PCA3 appears most useful in determine which patients should undergo repeat biopsy. For example, in a prospective multicenter clinical study of 466 men with at least 1 prior negative prostate biopsy, a PCA3 score cutoff of 25 showed a sensitivity of 78%, specificity of 57%, negative predictive value (NPV) of 90%,and PPV of 34%. Men with a score of ≥ 25 were 4.6 times more likely to have a positive repeat biopsy than those with a score < 25.

 

Results were reported from an NCI Early Detection Research Network (EDRN) validation study of the PCA3 urinary assay in 859 men scheduled for a diagnostic prostate biopsy in 11 centers. The primary outcomes reported at a PPV of 80% (95% CI, 72%-86%) in the initial biopsy setting and NPV of 88% (95% CI, 81%-93%) in the repeat biopsy setting. Based on the data, use of PCA3 in the repeat biopsy setting would reduce the number of biopsies by almost half, and 3% of men with a low PCA3 score would have high grade prostate cancer that would be missed. In contrast, the risk of high grade disease in men without prior biopsy with a low PCA3 is 13%. Thus, the panel believes that this test is not appropriate to use in the initial biopsy setting.

 

The FDA has approved the PCA3 assay to help decide, along with other factors, whether a repeat biopsy in men age 50 years or older with one or more previous negative prostate biopsies is necessary. This assay is recommended in men with previous negative biopsy in order to avoid repeat biopsy by the Molecular Diagnostic Services Program (MOiDX), and is therefore covered by CMS (Centers for Medicare and Medicaid Services) in this setting.

 

Prostate Health Index (PHI)

The Prostate Health Index (PHI) is a combination of the tPSA, fPSA and proPSA tests. In the multicenter study, it was noted to have approximately double the sensitivity of fPSA/tPSA for cancer detection in those with serum PSA concentrations between 2 and 10 ng/mL. In addition, the PHI correlated with cancer grade and had an area under the curve (AUC) of 0.72 for discrimination of high grade (Gleason ≥ 7) cancer from low grade cancer or negative biopsy. Another prospective cohort study calculated an AUC of 0.815 for the detection of high-grade (Gleason Score ≥ 7) prostate cancer. This study determined the optimal cutoff of PHI to be a score of 24, which should lead to 36% of biopsies avoided with approximately 2.5% of high grade cancers missed. Other studies have also shown that PHI can predict aggressive prostate cancer and has potential clinical utility.

 

The PHI was approved by the FDA in 2012 for use in those with serum PSA values between 4 and 10 ng/mL. A clinical utility study conducted at 4 large urology group practices showed that use of PHI was in fact associated with a decrease in biopsy procedures performed when compared to historical controls from the same physicians (36.4% vs 60.3%; P < 0.0001). Patients in the study had a normal DRE and PSA values ranging from 4 to 10 ng/mL. Physician survey results showed that PHI results impacted biopsy decisions in 73% of cases.

 

4KScore

The 4Kscore test is another combination test that measures free and tPSA, human kallikrein 2 (hK2), and intact PSA and also considers age, DRE results, and prior biopsy status. This test reports the percent likelihood of finding high-grade (Grade Group ≥ 2) cancer on biopsy. A prospective multi-institutional U.S> trial of 1012 patients showed that 4Kscore results have a high discrimination value (AUC, 0.82). In this study, using a threshold biopsy of ≥ 15% risk allosed for 591 biopsies to be avoided (58%), while 183 high-grade tumors were detected and 48 high grade tumors (4.7% of the 1012 participants) were missed. When 4Kscore was examined in 6129 men in another prospective study, the AUC was also 0.82 (95% CI, 0.80-0.84). Using a 6% risk of high-grade cancer cutoff, 428 of 1000 men could avoid biopsy, with 119 of 133 high grade cancers detected and 14 of 133 missed. A multi-center clinical utility study found a 65% reduction in prostate biopsies with use of 4Kscore test. In addition, a correlation between 4Kscore risk category and Gleason score was seen (P < .01). A meta-analysis that included 12 clinical validation studies (11,134 patients) led to a calculated pooled AUC for discrimination of prostate cancer with Gleason score of ≥ 7 of 0.81 (fixed effects 95% CI, 0.80-0.83).

 

The panel consensus is that the test can be considered for patients prior to biopsy and for those with prior negative biopsy for men thought to be at higher risk for clinically significant prostate cancer. It is important for patients and their urologists to understand, however, that no optimal cut-off threshold has been established for the 4Kscore. If a 4Kscore test is performed, the patient and his urologist should discuss the results to decide whether to proceed with a biopsy.

 

ConfirmMDx

ConfirmMDx is a tissue based, multiplex epigenetic assay that aims to improve the stratification of men being considered for repeat prostate biopsy. Hypermethylation of the promotor regions of GSTP1, APC, and RASSF1 are assessed in core biopsy tissue samples. The test, performed in on CLIA-certified laboratory, is not FDA approved.

 

The European MATLOC study blindly tested this assay in archived tissue from 498 men with negative biopsies who had repeat biopsies within 30 months. The NPV was 90% (95% CI, 87%-93%). In multivariate analysis, ConfirmMDx was predictive of patient outcome (OR, 3.17; 95% CI, 1.81-5.53). A similar validation study was performed in the United States using archived tissue from 350 men when negative biopsies who had repeat biopsies within 24 months. The NPV was 83% (95% CI, 85%-91%), and the test was again found to be predictive of outcomes on multivariate analysis (OR, 2.69; 95% CI, 1.60-4.51).

 

The panel believes that ConfirmMDx can be considered an option for men contemplating repeat biopsy because the assay may identify individuals at higher risk of prostate cancer diagnosis on repeat biopsy. This assay is approved for limited coverage by MoIDX for the reduction of unnecessary repeat prostate biopsies.

 

ExoDx Prostate (IntelliScore)

ExoDx Prostate (IntelliScore), also called EPI, evaluates a urine-based 3 gene exosome expression assay utilizing PCA3 and ERG (V-ets erythroblastosis virus E26 oncogene homologs) RNA from urine, normalized to SPDEF (SAM pointed domain-containing ETS transcription factor). The background for these markers is supported by a number of studies, but the application to exosome detection is unique. This gene panel proposes to discriminate Grade Group ≥ 2 prostate cancer from Grade Group 1 and benign disease at initial biopsy. The population for which use of the assay was intended includes patients older than 50 years with no prior biopsy and a PSA value between 2 and 10 ng/mL. In a recent study by McKiernan et. al., estimates of the AUC were similar in the training (0.74) and validation (0.71) cohorts for the assay, with significant improvements when the test was added to standard of care variables alone. Applying a cutoff value from the training cohort to serve as a threshold for biopsy in the validation cohort decreased the need for biopsy by 27% (138 of 519) while missing 8% (12 of 148) of Grade Group ≥ 2 cancers. The investigators propose the assay as a secondary or reflex test for risk stratification in conjunction with PSA screening. In the McKiernan study, the algorithm was validated in a test set of 255 patients and then validated in the extended screening validation cohort of 519 patients. The majority of exclusions were for urine volume > 49 mL, assay failure, and application outside the intended use population.

 

A second independent validation study was a 2 phase adaptive clinical utility study that included 503 biopsy-naive patients with PSA levels between 2 and 10 ng/mL and compared EPI and biopsy results. In the first phase of this study, the AUC was 0.70 for predicting Grade Group ≥ 2 cancer by EPI. Using the validated cut-point 15.6, the test has an NPV of 89%, reducing total biopsies by 20% and missing 7% of Grade Group ≥ 2 cancer. The second phase of this trial will be reported in the future.

 

The panel believes that EPI can be considered as an option for men contemplating initial or repeat biopsy.

 

Additional Biomarker Tests

The list of assays with the potential to permit improved detection of Grade Group ≥ 2 prostate cancers as an adjuvant to PSA screening is growing rapidly. Below, several of these assays are discussed. Given the lack of validation of the models/algorithms in additional, independent publications, their unclear behavior in other screened populations, and the lack of clarity regarding the incremental value and cost effectiveness of these assays, however, the panel cannot recommend their routine use at this time. Furthermore, potential sources of error in these approaches include undetectable cancers, as high as 25%, in patients with a single negative prostate biopsy. Other significant and unaddressed issues include the well-known upgrading (32%-49%) that occurs in patients with Gleason 6 cancer at biopsy at the time of pathologic assessment of the surgical specimen. Longer term follow-up of the cohorts to determine whether missed prostate cancers were ultimately detected is needed. In addition, validation of these tests in other cohorts of men is needed before they can be accepted as alternatives to (or perhaps preferable) other tests, described above.

 

Mi-Prostate Score

The Mi-Prostate Score (MiPS) assay measures total serum PSA and post DRE urine expression of PCA3 and the TMPRSS2-ERG fusion gene. Rearrangements of the ERG gene are found in approximately half of prostate cancers. The TMPRTSS2-ERG fusion specifically occurs at high frequency and appears to be an early event in prostate cancer development.

 

Based on reasons discussed above (See Additional Biomarker Tests), the panel considers MiPS to be investigational at the present time but will review additional information as it becomes available.

 

SelectMDx

SelectMDx is a gene expression assay performed on post DRE urine that measures DLX1 and HOXC6 expression against KLK3 as internal reference. DLX1 and HOXC6 have been associated with prostate cancer aggressiveness. As with other assays, SelectMDx is designed to improve the identification of men with clinically significant prostate cancer prior to biopsy, thereby reducing the number of unnecessary biopsies.

 

Based on reasons discussed above (See Additional Biomarker Tests), the panel considers SelectMDx to be investigational at the present time but will review additional information as it becomes available.

 

The current NCCN guideline does not include or indicate the use of the APIFINY biomarker testing, or gene panels or single nucleotide variant (SNVs) testing for prostate cancer risk assessment or management.

 

NCCN Recommendations

The decision to participate in an early detection program for prostate cancer is complex for both the patient and physician. Important factors must be assessed when considering early detection of prostate cancer, including patient age, life expectancy, family history, race, presence of inherited mutations, and previous early detection test results. Most importantly, the patient and physician need to understand the risks and benefits associated with the early detection and treatment of prostate cancer.

  • The panel recommends that consideration may be given to biomarkers that improve biopsy specificity such as percent free PSA (%free PSA), 4Kscore, and PHI before biopsy in men with serum PSA levels of > 3 ng/mL who desire more specificity. These tests ConfirmMDx and PCA3 are also options in men being considered for repeat biopsy after an initially benign result. Muliparametric MRI may be of similar value in both situations.

 

U.S. Preventative Services Task Force (USPSTF)

The U.S. Preventative Services Task Force (USPSTF) published an updated recommendation in 2018 for prostate cancer screening, and the recommendation does not address genetic or protein biomarker testing.

 

Prior Approval:

Not applicable

 

Policy:

See Related Medical Policy

  • 02.01.20 Serum Tumor Markers in the Management of Malignancies
  • 02.04.25 Prostate Specific Antigen Screening for Prostate Cancer
  • 02.04.57 Gene Expression Profiling and Protein Biomakers for Prostate Cancer Management
  • 02.04.64 Expanded Genetic Panels to Assess Cancer Risk 

Genetic and Protein Biomarkers

PCA3 (Progensa PCA3 assay/Prostate Cancer Gene 3 [PCA3]) (81313)

PCA3 (Progensa PCA3 assay/Prostate Cancer Gene 3 [PCA3] is considered medically necessary to aid in the decision regarding a repeat prostate biopsy when ALL of the following criteria are met:

  • Age ≥ 50 years; AND
  • One or more previous negative prostate biopsies; OR
  • A previous prostate biopsy that shows focal high-grade prostatic intraepithelial neoplasia (PIN); AND
  • Atypical small acinar proliferation (ASAP) was NOT identified on the most recent prostate biopsy; AND
  • Continued clinical suspicion of prostate cancer based on digital rectal exam (DRE) (the individuals DRE was not performed within 96 hours (4 days) prior to this testing which may be associated with secondary PSA elevation) or elevation of prostate specific antigen (PSA) > 3 ng/mL, and for whom a repeat biopsy would be recommended by a urologist based on current standard of care; AND
  • The individual has not undergone any procedure or therapy to treat symptomatic BPH (benign prostatic hypertrophy) or any invasive urological procedure that may be associated with secondary PSA elevation within the last 6 months.

 

4Kscore Test (81539 and 0011M)

4Kscore Test is considered medically necessary when ALL of the following criteria are met:

  • The test will be performed prior to an initial prostate biopsy; OR
  • The individual has had a prior negative prostate biopsy; AND
  • The individual is ≥ 40 years of age; AND
  • Continued clinical suspicion of prostate cancer based on elevation of prostate specific antigen (PSA) > 3 ng/mL, and for whom an initial prostate biopsy or repeat prostate biopsy would be recommended by a urologist based on current standard of care; AND
  • The individual is considered at higher risk for prostate cancer by one or more of the following:
    • Family history of a first degree relative (close blood relative parent, full sibling(s) or children) with prostate cancer diagnosed younger than 65 years; and/or
    • African American race; and/or
    • Known mutation in a gene associated with increased risk of prostate cancer (e.g. BRCA 1/2, MLH1, MSH2, MHS6, PMS2, EPCAM); AND 
  • The individual has not taken 5-alpha reductase inhibitors (5-ARI) within the last 6 months (such as Avodart [dutasteride] or Proscar [finasteride]); AND
  • The individual has not undergone any procedure or therapy to treat symptomatic BPH (benign prostatic hypertrophy) or any invasive urological procedure that may be associated with secondary PSA elevation within the last 6 months; AND
  • The individual has not received a digital rectal exam in the previous 96 hours (4 days) prior to this testing which may be associated with secondary PSA elevation.

 

Prostate Health Index (PHI) (P2PSA) (86316)

Prostate Health Index (PHI) is considered medically necessary when ALL of the following criteria are met:

  • Age ≥ 50 years of age; AND
  • The test will be performed prior to an initial prostate biopsy; AND
  • Continued clinical suspicion of prostate cancer based on elevation of prostate specific antigen (PSA) > 3 ng/mL, and for whom a prostate biopsy would be recommended by a urologist based on current standard of care ; AND
  • Digital rectal exam (DRE) findings are not suspicious for prostate cancer.

 

ExoDx Prostate (IntelliScore) (0005U)

ExoDx Prostate (IntelliScore) is considered medically necessary when ALL of the following criteria are met:

  • Age ≥ 50 years of age; AND
  • The test will be performed prior to an initial prostate biopsy; OR
  • The individual has had a prior negative prostate biopsy; AND
  • Continued clinical suspicion of prostate cancer based on elevation of prostate specific antigen (PSA) >3 ng/mL, and for whom an initial prostate biopsy or repeat prostate biopsy would be recommended by a urologist based on current standard of care.

 

ConfirmMDx (81551)

ConfirmMDx is considered medically necessary to reduce an unnecessary repeat biopsy when ALL of the following criteria are met:

  • Age ≥ 40 years of age; AND
  • Prior negative prostate biopsy; AND
  • Prior biopsy histology does not include a cellular atypia suspicious for cancer, but may include the presence of high-grade prostatic intraepithelial neoplasia, proliferative inflammatory atrophy or glandular inflammation; AND
  • Continued clinical suspicion of prostate cancer based on elevation of prostate specific antigen (PSA) > 3 ng/mL; AND
  • The individual is considered at higher risk for prostate cancer by one or more of the following:
    • Family history of a first degree relative (close blood relative parent, full sibling(s) or children) with prostate cancer diagnosed younger than 65 years; and/or
    • African American race; and/or
    • Known mutation in a gene associated with increased risk of prostate cancer (e.g. BRCA 1/2, MLH1, MSH2, MHS6, PMS2, EPCAM).

 

PCA3 (Progensa PCA3 assay/Prostate Cancer Gene 3 [PCA3]), 4Kscore Test, Prostate Health Index (PHI) (pro2PSA), ConfirmMDx or ExoDx Prostate IntelliScore not meeting the above criteria is considered investigational, there is insufficient evidence to support a conclusion concerning net health outcomes or benefits associated for this testing for all other indications.

 

Genetic and protein biomarkers including but not limited to the following, for the risk assessment and diagnosis of prostate cancer are considered investigational.

  • APIFINY
  • TMPRSS fusion genes
  • Prostate Core Mitomics Test (PCMT)/Mitochondrial DNA mutation testing
  • Mi-Prostate Score (MiPS)
  • SelectMDx for Prostate Cancer

 

To date, the majority of available studies fail to provide sufficient evidence that the above genetic and protein biomarker testing for the cancer risk assessment and diagnosis of prostate cancer leads to improved net health outcomes or a change in management treatment decisions (i.e. clinical utility). Well - designed randomized controlled trials (RCTs) are needed to determine the clinical utility of these genetic and protein biomarker tests for the cancer risk assessment and diagnosis of prostate cancer compared to traditional clinical factors/testing to guide medical management and improve clinical outcomes. The NCCN guideline version 2.2019 Prostate Cancer Early Detection does not recommend the use of this testing to aid in the decision making in regards to proceeding with an initial prostate biopsy or to determine the need for repeat prostate biopsy. The evidence is insufficient to determine the effects of the above testing on net health outcomes.

 

Expanded Gene Panels and Single Nucleotide Variant Testing (SNVs)

Expanded gene panels and single nucleotide variant (SNVs) testing for cancer risk assessment of prostate cancer is considered investigational.

 

Numerous studies have demonstrated the association of many gene panels and single nucleotide variant testing (SNVs) with prostate cancer. These studies, in early stages of development, have generally shown a modest degree of association with future risk for prostate cancer. The clinical utility of these tests is uncertain; there is no evidence that information obtained from gene panels and single nucleotide variant (SNVs) testing can be used to change management in ways that improve net health outcomes. The evidence is insufficient to determine the effects of the above testing on net health outcomes.

 

Policy Guidelines

Clinically Localized Prostate Cancer AUA/ASTRO/SUO Guideline

Active Surveillance
  • Localized prostate cancer patients who elect active surveillance should have accurate disease staging including systematic biopsy with ultrasound or MRI guided imaging. (Clinical Principle)
  • Localized prostate cancer patients undergoing active surveillance should have routine surveillance PSA testing and digital rectal exams (DRE). (Strong recommendation)
  • Localized prostate cancer patients undergoing active surveillance should be encouraged to have confirmatory biopsy within the initial two years and surveillance biopsies thereafter. (Clinical Principle)
  • Clinicians should offer definitive treatment to localized prostate cancer patients undergoing active surveillance who develop adverse reclassification. (Moderate Recommendation)

 

See also Wellmark Medical Policy 02.04.25 Prostate-Specific Antigen Screening for Prostate Cancer:

 

Based on the policy criteria of this medical policy prostate cancer screening using PSA may be considered medically necessary in the following high risk individuals:

  • Asymptomatic men 40-49 years of age who are at high risk of prostate cancer due to any of the following factors:
    • African-American race; or
    • More than one first degree relative (father, full sibling (brother), or son) diagnosed with prostate cancer at an early age (younger than age 65).

 

The medically necessary criteria above for 4Kscore test and ConfirmMDx that requires a higher risk for prostate cancer aligns with the above guideline in medical policy 02.04.25 as to when it would be appropriate to begin screening for prostate cancer in this population of men to assess the need for further management with prostate biopsy dependent on results with active surveillance.

 

Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes and / or diagnosis codes.

  • 81229 Interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants for chromosomal abnormalities
  • 81313 PCA3/KLK3 (prostate cancer antigen 3 [non-protein coding]/kallikrein-related peptidase 3 [prostate specific antigen] ratio (eg, prostate cancer)
  • 81479 Unlisted molecular pathology procedure (when specified for one of the following: Prostate Core Mitomics Testing (PCMT); or TMPRSS Fusion Genes; or SelectMDx or SelectMDx Prostate Cancer)
  • 81539 Oncology (high grade prostate cancer), biochemical assay of four proteins (Total PSA, Free PSA, Intact PSA, and human kallikrein-2 [hK2], utilizing plasma or serum, prognostic algorithm reported as probability score (4Kscore Test)
  • 81551 Oncology (prostate), promoter methylation profiling by real-time PCR of 3 genes (GSTP1, APC, RASSF1), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a likelihood of prostate cancer detection on repeat biopsy (ConfirmMDx)
  • 81599 Unlisted multianalyte assay with algorithmic analysis (when specified for one of the following: Prostate Core Mitomics Testing (PCMT); or TMPRSS Fusion Genes; or SelectMDx or SelectMDx Prostate Cancer)
  • 86316 Immunoassay for tumor antigen, other antigen, quantitative, (e.g. CA 50, 72-4. 549) each. (PerA Coding and Reimbursement Committee this CPT should be used for the calculation of Prostate Health Index (phi) value and immunoassay component pro2PSA)
  • 0011M Oncology, prostate cancer, mRNA expression assay of 12 genes (10 content and 2 housekeeping), RT-PCR test utilizing blood plasma and/or urine, algorithms to predict high grade cancer risk (4Kscore Test)
  • 0005U Oncology (prostate) gene expression profile by real time RT-PCR of 3 genes (ERG, PCA3, and SPDEF), urine algorithm reported as risk score (ExoDx Prostate (IntelliScore)/ExosomeDx Prostate (IntelliScore)
  • 0021U Oncology (prostate) detection of 8 autoantibodies (ARF 6, NKX3-1, 5-UTR-BMI1, CEP 164, 3-UTR-Ropporin, Desmocollin, AURKAIP-1, CSNK2A2), multiplexed immunoassay and flow cytometry serum, algorithm reported as risk score (APIFINY)
  • 0113U Oncology (prostate), measurement of PCA3 and TMPRSS2-ERG in urine and PSA in serum following prostatic massage, by RNA amplification and fluorescence-based detection, algorithm reported as risk score (MiPS [Mi-Prostate Score)

 

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  • Boegemann M, Stephan C, Cammann H, et al. The percentage of prostate-specific antigen (PSA) isoform [-2]proPSA and the Prostate Health Index improve the diagnostic accuracy for clinically relevant prostate cancer at initial and repeat biopsy compared with total PSA and percentage free PSA in men aged </=65 years. BJU Int. Jan 2016;117(1):72-79. PMID 25818705
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  • APIFINY Armune Biosciences.
  • ExoDX Prostate (IntelliScore).
  • Mi-Prostate Score (MIPS).
  • SelectMDx for Prostate Cancer.
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  • Food and Drug Administration. Summary of Safety and Effectiveness Data. PMA P090026. Quantitative test for determination of [-2]proPSA levels. Silver Spring, MD: Food and Drug Administration; 2012.
  • Bruzzese D, Mazzarella C, Ferro M, et al. Prostate health index vs percent free prostate-specific antigen for prostate cancer detection in men with "gray" prostate-specific antigen levels at first biopsy: systematic review and meta-analysis. Transl Res. Dec 2014;164(6):444-451. PMID 25035153
  • Wang W, Wang M, Wang L, et al. Diagnostic ability of %p2PSA and prostate health index for aggressive prostate cancer: a meta-analysis. Sci Rep. May 23 2014;4:5012. PMID 24852453
  • National Institute for Health and Care Excellence (NICE). Diagnosing prostate cancer: PROGENSA PCA3 assay and Prostate Health Index [DG17]. 2015
  • Filella X, Gimenez N. Evaluation of [-2] proPSA and Prostate Health Index (phi) for the detection of prostate cancer: a systematic review and meta-analysis. Clin Chem Lab Med. Apr 2013;51(4):729-739. PMID 23154423
  • Fossati N, Lazzeri M, Haese A, et al. Clinical performance of serum isoform [-2]proPSA (p2PSA), and its derivatives %p2PSA and the Prostate Health Index, in men aged <60 years: results from a multicentric European study. BJU Int. Jun 2015;115(6):913-920. PMID 24589357
  • Boegemann M, Stephan C, Cammann H, et al. The percentage of prostate-specific antigen (PSA) isoform [-2]proPSA and the Prostate Health Index improve the diagnostic accuracy for clinically relevant prostate cancer at initial and repeat biopsy compared with total PSA and percentage free PSA in men aged </=65 years. BJU Int. Jan 2016;117(1):72-79. PMID 25818705
  • Morote J, Celma A, Planas J, et al. Diagnostic accuracy of prostate health index to identify aggressive prostate cancer. An Institutional validation study. Actas Urol Esp. Jul-Aug 2016;40(6):378-385. PMID 26923032
  • Yu GP, Na R, Ye DW, et al. Performance of the Prostate Health Index in predicting prostate biopsy outcomes among men with a negative digital rectal examination and transrectal ultrasonography. Asian J Androl. Jul-Aug 2016;18(4):633-638. PMID 26975483
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  • Food and Drug Administration. Summary of Safety and Effectiveness Data. PMA P100033: PROGENSA PCA3 Assay. Silver Spring, MD: Food and Drug Administration; 2012.
  • Bradley LA, Palomaki G, Gutman S, et al. PCA3 Testing for the Diagnosis and Management of Prostate Cancer (Comparative Effectiveness Reviews No. 98). Rockville, MD: Agency for Healthcare Research and Quality; 2013.
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  • Wei JT, Feng Z, Partin AW, et al. Can urinary PCA3 supplement PSA in the early detection of prostate cancer? J Clin Oncol. Dec 20 2014;32(36):4066-4072. PMID 25385735
  • Ankerst DP, Groskopf J, Day JR, et al. Predicting prostate cancer risk through incorporation of prostate cancer gene 3. J Urol. Oct 2008;180(4):1303-1308; discussion 1308. PMID 18707724
  • Chun FK, de la Taille A, van Poppel H, et al. Prostate cancer gene 3 (PCA3): development and internal validation of a novel biopsy nomogram. Eur Urol. Oct 2009;56(4):659-667. PMID 19304372
  • Perdona S, Cavadas V, Di Lorenzo G, et al. Prostate cancer detection in the "grey area" of prostate-specific antigen below 10 ng/ml: head-to-head comparison of the updated PCPT calculator and Chun's nomogram, two risk estimators incorporating prostate cancer antigen 3. Eur Urol. Jan 2011;59(1):81-87. PMID 20947244
  • Haese A, de la Taille A, van Poppel H, et al. Clinical utility of the PCA3 urine assay in European men scheduled for repeat biopsy. Eur Urol. Nov 2008;54(5):1081-1088. PMID 18602209
  • Nakanishi H, Groskopf J, Fritsche HA, et al. PCA3 molecular urine assay correlates with prostate cancer tumor volume: implication in selecting candidates for active surveillance. J Urol. May 2008;179(5):1804-1809; discussion 1809-1810. PMID 18353398
  • Whitman EJ, Groskopf J, Ali A, et al. PCA3 score before radical prostatectomy predicts extracapsular extension and tumor volume. J Urol. Nov 2008;180(5):1975-1978; discussion 1978-1979. PMID 18801539
  • Bostwick DG, Gould VE, Qian J, et al. Prostate cancer detected by uPM3: radical prostatectomy findings. Mod Pathol. May 2006;19(5):630-633. PMID 16528369
  • van Gils MP, Hessels D, Hulsbergen-van de Kaa CA, et al. Detailed analysis of histopathological parameters in radical prostatectomy specimens and PCA3 urine test results. Prostate. Aug 1 2008;68(11):1215-1222. PMID 18500693
  • Auprich M, Chun FK, Ward JF, et al. Critical assessment of preoperative urinary prostate cancer antigen 3 on the accuracy of prostate cancer staging. Eur Urol. Jan 2011;59(1):96-105. PMID 20980098
  • Tosoian JJ, Loeb S, Kettermann A, et al. Accuracy of PCA3 measurement in predicting short-term biopsy progression in an active surveillance program. J Urol. Feb 2010;183(2):534-538. PMID 20006883
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  • Suh CI, Shanafelt T, May DJ, et al. Comparison of telomerase activity and GSTP1 promoter methylation in ejaculate as potential screening tests for prostate cancer. Mol Cell Probes. Aug 2000;14(4):211-217. PMID 10970725
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  • Henrique R, Jeronimo C, Teixeira MR, et al. Epigenetic heterogeneity of high-grade prostatic intraepithelial neoplasia: clues for clonal progression in prostate carcinogenesis. Mol Cancer Res. Jan 2006;4(1):1-8. PMID 16446401
  • Eilers T, Machtens S, Tezval H, et al. Prospective diagnostic efficiency of biopsy washing DNA GSTP1 island hypermethylation for detection of adenocarcinoma of the prostate. Prostate. May 15 2007;67(7):757-763. PMID 17373715
  • Ellinger J, Albers P, Perabo FG, et al. CpG island hypermethylation of cell-free circulating serum DNA in patients with testicular cancer. J Urol. Jul 2009;182(1):324-329. PMID 19447423
  • Henrique R, Ribeiro FR, Fonseca D, et al. High promoter methylation levels of APC predict poor prognosis in sextant biopsies from prostate cancer patients. Clin Cancer Res. Oct 15 2007;13(20):6122-6129. PMID 17947477
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  • Ellinger J, Bastian PJ, Jurgan T, et al. CpG island hypermethylation at multiple gene sites in diagnosis and prognosis of prostate cancer. Urology. Jan 2008;71(1):161-167. PMID 18242387
  • Sunami E, Shinozaki M, Higano CS, et al. Multimarker circulating DNA assay for assessing blood of prostate cancer patients. Clin Chem. Mar 2009;55(3):559-567. PMID 19131636
  • Kachakova D, Mitkova A, Popov E, et al. Evaluation of the clinical value of the newly identified urine biomarker HIST1H4K for diagnosis and prognosis of prostate cancer in Bulgarian patients. J BUON. Jul-Sep 2013;18(3):660-668. PMID 24065480
  • Goessl C, Muller M, Heicappell R, et al. Methylation-specific PCR for detection of neoplastic DNA in biopsy washings. J Pathol. Mar 2002;196(3):331-334. PMID 11857497
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  • Mehrotra J, Varde S, Wang H, et al. Quantitative, spatial resolution of the epigenetic field effect in prostate cancer. Prostate. Feb 1 2008;68(2):152-160. PMID 18058812
  • Van Neste L, Bigley J, Toll A, et al. A tissue biopsy-based epigenetic multiplex PCR assay for prostate cancer detection. BMC Urol. Jun 06 2012;12:16. PMID 22672250
  • Aubry W, Lieberthal R, Willis A, et al. Budget impact model: epigenetic assay can help avoid unnecessary repeated prostate biopsies and reduce healthcare spending. Am Health Drug Benefits. Jan 2013;6(1):15-24. PMID 24991343
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  • Tomlins SA, Day JR, Lonigro RJ, et al. Urine TMPRSS2:ERG Plus PCA3 for Individualized Prostate Cancer Risk Assessment. Eur Urol. Jul 2016;70(1):45-53. PMID 25985884
  • Prostate Core Mitomic Test: Clinical insight.
  • Parr RL, Dakubo GD, Crandall KA, et al. Somatic mitochondrial DNA mutations in prostate cancer and normal appearing adjacent glands in comparison to age-matched prostate samples without malignant histology. J Mol Diagn. Jul 2006;8(3):312-319. PMID 16825503
  • Palmetto GBA. MoIDX Hub. Progensa PCA3 Assay Coding and Billing Guidelines (M00013, V6).
  • Maki J, Robinson K, Reguly B, et al. Mitochondrial genome deletion aids in the identification of false- and true-negative prostate needle core biopsy specimens. Am J Clin Pathol. Jan 2008;129(1):57-66. PMID 18089489
  • U.S. Preventative Services Task Force (USPSTF) 2018 Recommendation for Prostate Cancer Screening.
  • Sanda M, Chen R, Crispino T, et. al. Clinically Localized Prostate Cancer: AUA/ASTRO/SUO Guideline. Approved by the American Urological Association Board of Directors April 2017.
  • Carter HB, Albertsen P, Barry M, et. al. American Urological Association Guideline for Early Detection of Prostate Cancer. Approved by the AUA Board of Directors April 2013, guideline was re-reviewed and confirmed as current June 2018.
  • Carroll P, Albertsen P, Greene K, et. al. PSA Testing for the Pretreatment Staging and Post-Treatment Management of Prostate Cancer. American Urological Association. 2013 revision of 2009 best practice statement.
  • Metamark PCA3.
  • FDA Summary of Safety and Effectiveness Data (SSED) Prostate Health Index (PHI)/2proPSA.
  • Mayo Clinic Medical Laboratories. The Prostate Health Index (PHI).
  • MoIDX 4Kscore Assay Local Coverage Determination (L36763)
  • MoIDX ConfirmMDx Local Coverage Determination (L35632)
  • ConfirmMDx for Prostate Cancer.
  • Chen R, Rumble RB, Loblaw DA, et. al. Active Surveillance for the Management of Localized Prostate Cancer (Cancer Care Ontario Guideline): American Society of Clinical Oncology Clinical Practice Guideline Endorsement. Journal of Clinical Oncology Volume 34, Number 18 June 20, 2016    
  • National Institute for Health and Clinical Excellence. Prostate Cancer: Diagnosis and Management. NG131 Published May 2019.
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  • Aubry W. Liberthal R, Willis A, et. al. Budget impact model: epigenetic assay can help avoid unnecessary repeated prostate biopsies and reduce healthcare spending. Am Health Drug Benefits. Jan 2013;6(1):15-24. PMID 24991343
  • Partin AW, W Vanc, Trock BN, et. al. Clinical evaluation of an epigenetic assay to predict missed cancer in prostate biopsy specimens. Trans Am Clin Climatol Assoc 2016;127:313-327. PMID 28066067
  • Waterhouse RL, Van Neste L, Mosses KA, et. al. Evaluation of an epigenetic assay for predicting repeat prostate biopsy outcome in African American men. Urology 2019 Jun;128:62-65. PMID 29660369   
  • Partin AW, Van Neste L, Klein EA, et. al. Clinical validation of an epigenetic assay to predict negative histopathological results in repeat prostate biopsies. J Urol Oct 2014;192(4):1081-1087. PMID 24747657
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  • Russo GI, Regis F, Castelli T, et. al. A systematic review and meta-analysis of the diagnostic accuracy of Prostate Health Index in patients with a prior negative biopsy: a consensus statement by AUA and SAR. J Urol Dec 2016;196(6);1613-1618. PMID 28111174
  • McKiernan J, Donovan M, Margolis E, et. al. A prospective adaptive utility trial to validate performance of a novel urine exosome gene expression assay to predict high- gr ade prostate cancer in patients with prostate specific antigen 2-10 ng/ml at initial biopsy. European Urology 74 (2018) 731-738

 

Policy History:

  • June 2020 - Annual Review, Policy Renewed
  • December 2019 - Interim Review, Policy Revised
  • June 2019 - Annual Review, Policy Revised
  • June 2018 - Annual Review, Policy Revised
  • October 2017 - Interim Review, Policy Revised
  • June 2017 - Annual Review, Policy Revised
  • June 2016 - Policy revised and new policy created

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

*CPT® is a registered trademark of the American Medical Association.